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We report the results of a prospective trial aimed at describing the feasibility and accuracy of prostate-specific membrane antigen (PSMA) radio-guided surgery (RGS) during robot-assisted radical prostatectomy (RARP) with extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa). This was a phase 2 study (NCT04832958) that enrolled 82 patients with localized PCa and a lymph node invasion (LNI) risk >5%. All patients underwent preoperative PSMA positron emission tomography (PET). [99mTc]Tc-PSMA-I&S was administered intravenously the day before surgery, followed by single-photon emission computed tomography/computed tomography. Side effects, perioperative outcomes, and the performance characteristics of PSMA-RGS for LNI detection were measured. A total of 62 patients completed all study procedures and were included in the final analyses. Median blood loss and length of stay were 50 ml and 4 d, respectively. No adverse events after tracer administration or intraoperative complications were recorded. Four patients experienced a Clavien-Dindo grade 3 complication within 30 d. Overall, PSMA-RGS identified two additional patients with high-risk PCa and pathologically node-positive (pN1) disease compared with preoperative PSMA PET, exhibiting a lower positive predictive value (PPV) and a similar negative predictive value (NPV) in the per-patient analysis (PPV: 50% vs 70%; NPV: 83% vs 83%). The PPV and NPV at per-region analysis in patients with molecular imaging node-positive (miN1) disease were higher for PSMA-RGS than for PSMA PET (PPV: 55% vs 42%; NPV: 85% vs 81%). In conclusion, PSMA-RGS identifies additional patients with pN1 disease missed by preoperative PSMA-PET among men with high-risk PCa, and extends the ePLND template in patients with miN1 disease, in whom PSMA PET underestimates the nodal burden. However, its NPV is suboptimal for avoiding ePLND in patients with PCa who have a LNI risk >5% and negative PSMA-RGS findings during RARP.

The purpose of this study was to compare the image quality and lesion detection between ultra-low dose (ULD) chest-abdomen-pelvis computed tomography (CAP-CT) reconstructed with a deep-learning image reconstruction (DLR) algorithm, and standard-dose CT (STD-CT) in cancer follow-up. A total of 106 patients undergoing CAP-CT for the follow-up of cancer were prospectively included. Each patient underwent both STD-CT and ULD-CT acquisitions. ULD-CT images were reconstructed using two DLR levels (Smooth/Smoother). Dosimetric indicators, objective image quality, subjective image quality, and lesion detection were compared. Agreement between protocols and readers was assessed using Gwet's AC1 or AC2 coefficients. ULD-CT significantly reduced radiation exposure, with a mean CTDIvol reduction of -71.5% and dose-length product reduction of -71.5% (P < 0.05). Minor but statistically significant differences in HU values were observed between STD-CT and ULD-CT across most tissues. For all organs or tissues, image noise was significantly higher with ULD-CT-Smooth than with STD-CT (P < 0.001), and with ULD-CT-Smoother than with STD-CT, except for dorsal vertebra (P = 0.39) and trachea (P = 0.26). For all organs or tissues, image noise was significantly lower with the Smoother DLR level than with Smooth DLR level (P < 0.001). Agreement between STD-CT and ULD-CT regarding lesion detection was almost perfect for thoracic, abdominal, and bone lesions. Detection of infracentimetric hepatic was lower with ULD-CT, whereas detection of larger lesions (≥ 10 mm) remained similar. Subjective image quality was lower with ULD-CT, with moderate inter-reader agreement, and lower diagnostic confidence than with STD-CT. One of the two readers considered that 19%-24% of ULD-CT examinations were uninterpretable. ULD-CT with DLR offers substantial radiation dose reduction but resulted in poorer image quality and lower detection of small low-contrast abdominal lesions compared with STD-CT. Although lesion detection remained equivalent for thoracic and skeletal lesions, the high proportion of suboptimal or uninterpretable examinations may limit routine use of ULD protocols in cancer follow-up.

The rapid expansion of immuno-oncology (I-O) and other advanced therapies is reshaping the complexity of early-phase clinical development. While core Phase I principles remain fundamental across oncology, emerging modalities introduce additional requirements for translational integration, specialized safety management, and therapeutic-specific infrastructure. However, the organizational functions of Phase I units have not evolved at the same pace and remain largely centered on conventional operational responsibilities. Drawing on the practices of leading Phase I units across the USA, Europe, and China, and comparing evolving regulatory frameworks of the US Food and Drug Administration, European Medicines Agency/Medicines and Healthcare products Regulatory Agency, and China's National Medical Products Administration, we propose a global perspective on the future development of Phase I units. We present a three-layer framework encompassing core Phase I foundations applicable across oncology, advanced translational capabilities, and ecosystem-level functions supporting emerging therapeutic development. Beyond ensuring patient safety and high-quality trial conduct, modern Phase I units should integrate translational research, artificial intelligence-enabled and model-informed drug development, regulatory science, and public engagement, while specialized centers may additionally support advanced therapy infrastructure, such as point-of-care manufacturing. Recognizing the diversity of institutional resources, we further propose a collaborative network model to facilitate scalable implementation and international harmonization. This framework positions Phase I units as integrated platforms connecting clinical investigation, translational science, regulatory innovation, and emerging therapy development, providing practical guidance for building future-ready early-phase clinical research infrastructure worldwide.

Relapsed or refractory CNS lymphoma (R/R CNSL) has limited treatment options. This multicenter retrospective study enrolled 84 consecutive R/R CNSL patients (median age 59 years; 53 PCNSL, 31 SCNSL) to evaluate efficacy and safety profiles of glofitamab therapy. With a median of 2.5 prior lines of therapy, the objective response rates (ORR) and complete response rates (CRR) for PCNSL were 88% (CRR 59%) with glofitamab monotherapy (n=32) and 100% (CRR 81%) with combination therapy (n=21), respectively; for SCNSL, ORR and CRR were 88% (CRR 75%) with glofitamab monotherapy (n=8) and 91% (CRR 65%) with combination therapy (n=23). At 14.7 months follow-up, median progression-free survival was 19.5 months for PCNSL and 13.5 months for SCNSL. Cytokine release syndrome occurred in 40% (all grade 1-2) of patients, and ICANS in 8%. Glofitamab-based therapy demonstrated substantial activity with manageable toxicity in this study, offering a promising treatment paradigm for R/R CNSL patients.

Relapsed and/or refractory disease remains the leading cause of death in AML, highlighting the need for broadly applicable, high-sensitivity approaches to MRD detection. We developed AML-CAPP-Seq (Cancer Personalized Profiling by Deep Sequencing), a personalized hybrid-capture assay that tracks both canonical AML drivers and patient-specific variants identified by whole-exome sequencing. In 56 patients with longitudinal plasma and matched peripheral blood and bone marrow samples, AML-CAPP-Seq enabled universal MRD assessment and resolution of clonal dynamics using a median of 30.5 variants per patient. Plasma ctDNA outperformed cellular compartments for MRD detection and more strongly predicted relapse-free (HR 17.8, p<0.0001) and overall survival (HR 17.0, p<0.0001) than standard-of-care MRD methods. Among 29 allogeneic transplant recipients, peri-transplant ctDNA-MRD dynamics markedly improved relapse risk stratification (HR 36.0, p=0.0009). Together, these results establish personalized ctDNA profiling as a minimally invasive, highly sensitive, and generalizable platform for enhanced clinical MRD detection and clonal surveillance in AML.

Central nervous system (CNS) tumors represent the leading cause of pediatric cancer-related deaths. Primary treatment often involves neurosurgical tumor resection. Accurate diagnosis is crucial to perform the best-suited extent of resection. Recently, we published Sturgeon, an AI-based validated intraoperative nanopore sequencing tool, delivering accurate methylation-based diagnoses during surgery. Although several other nanopore sequencing strategies have been described, clear evidence of clinical impact remains critically absent. Here, we report a care evaluation analyzing the impact of Sturgeon on real-time pediatric neurosurgical decision-making. Since May 2023, a dual diagnostic neuro-oncological workflow incorporating intraoperative frozen section analyses and ultra-fast nanopore sequencing using Sturgeon has been fully implemented as standard of care at the Princess Máxima Center for Pediatric Oncology in the Netherlands. This intraoperative diagnostic workflow has been applied to all pediatric patients (<19 years of age) with primary CNS tumors and the multidisciplinary indication for tumor resection surgery. Sturgeon delivered correct diagnoses in 82 out of 94 consecutive patients (87.2%, <90 minutes), no diagnosis in 11.7% and one incorrect diagnosis (1.1%). The diagnosis obtained by Sturgeon supported the intended surgical strategy (85.7%) or changed the strategy (14.3%) toward a more aggressive or limited resection. This contributed to a low complication rate and less second-look surgeries. Earlier communication of the histomolecular diagnosis to patients and their families was observed. Intraoperative use of Sturgeon provides essential guidance toward the most optimal neurosurgical strategy for pediatric CNS tumors and thereby has great potential to contribute to better clinical outcome.

Chimeric antigen receptor (CAR) T cell therapy induces durable remissions in lymphoid malignancies, yet the extent and biology of long-term CAR T cell persistence in B cell lymphoma remain unclear. Here we report the persistence and characteristics of 4-1BB-costimulated anti-CD19 CAR T cells (CART19) up to 10 years after infusion in 38 patients with non-Hodgkin lymphoma. Beyond year five, the CAR19 transgene was detectable in five of eight long-term responders (7.0-10.1 years), with three patients maintaining B cell aplasia, which is consistent with sustained functional activity. In one patient with a progression-free survival of 10.1 years, CART19 cells comprised 1.2% of circulating T cells 9.3 years after infusion. Long-term persisting CART19 cells exhibited a predominant double-negative (CD4-CD8-), effector-memory-like phenotype associated with increased aerobic metabolism and T cell activation programs. Longitudinal profiling revealed a progressive transition from CD8+ to double-negative CAR T cells over time. Persisting CART19 shared transcriptional features with long-term CAR T cells described in acute and chronic leukemias. T cell receptor sequencing demonstrated oligoclonal persistence at 9.3 years, with a dominant clone (70% of CART19 cells) already detectable at low frequency (<0.1%) at day 14. Lentiviral integration-site analysis identified a predominant integration within PACS1 without evidence of known drivers of CAR T cell expansion. These findings demonstrate that CART19 cells can persist for more than 10 years in lymphoma and identify phenotypic, transcriptional and clonal features associated with exceptionally long-term persistence. ClinicalTrials.gov registration: NCT02030834.

T cell-mediated immune surveillance is critical for cancer control, yet its role in bone marrow malignancies remains poorly understood. Here, we integrate TCR profiling, HLA immunopeptidomics, and functional screening to characterize tumor-reactive T cells in the bone marrow of patients with multiple myeloma (MM) and acute myeloid leukemia (AML). These cells are transcriptionally defined by a conserved effector program distinct from the exhausted phenotype of tumor-reactive T cells in solid cancers. Immunopeptidomic profiling reveals a partially shared antigen landscape enriched for noncanonical peptides driving convergent TCR responses. We develop TFiT (tumor-reactive features in T cells), a transcriptional classifier that identifies these cells and stratifies immunotherapy, but not chemotherapy, response across independent MM and AML cohorts, supporting its specificity for T cell-mediated tumor control. These findings reveal a latent but activatable anti-tumor T cell compartment in bone marrow malignancies and provide a framework for engaging endogenous immunity in MM and AML.

PLATFORM is a prospective, open-label, multicentre, adaptive phase II trial assessing maintenance therapy in patients with advanced HER2-negative oesophagogastric adenocarcinoma after platinum-based first-line chemotherapy. After 18 weeks of platinum-based chemotherapy, patients with response or stable disease were randomised to surveillance (4 weekly visits) or rucaparib 600 mg tablet twice daily every 28 days. The primary endpoint was progression-free survival (PFS) (prespecified P value of 0.025). Secondary endpoints were safety and overall survival (OS). Exploratory translational analyses of homologous recombination deficiency (HRD) and somatic gene profiling are also reported. A total of 125 patients were randomised (surveillance: 62, rucaparib: 63). The median follow-up was 41 months. Median PFS was 2.8 months for surveillance and 4.2 months for rucaparib [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.49-1.02, P = 0.031]. There was no difference in OS (HR 1.15, 95% CI 0.77-1.72, P = 0.247). Grade ≥3 adverse events (AEs) occurred in 23% of surveillance and 32% of rucaparib patients. Treatment-related AEs were reported in 84% of patients in the rucaparib arm; 22% of which were grade 3-4. Most frequent grade 3-4 AEs were anaemia, fatigue, infection, and neutropenia. Adequate tissue for HRD analysis was available in 51/125 (40.8%) patients (surveillance: 20, rucaparib: 31). Five patients (9.8%) were HRD-positive, 41 (80.4%) HRD-negative, and 5 (9.8%) had inconclusive results. Among HRD-positive patients, four were treated with rucaparib and had PFS durations of 2.6, 3.0, 8.3, and 10.6 months, respectively. TP53 was the most frequently detected somatic alteration, followed by SMARCA4 and ARID1A. Compared with surveillance, maintenance rucaparib following first-line chemotherapy in patients with advanced HER2-negative OGA did not significantly improve PFS with no observed difference in OS. Translational analyses were limited by small sample size, and no clear associations with clinical outcomes were identified.

PAX5-altered acute lymphoblastic leukemia (PAX5-alt ALL) is a recently recognized molecular subtype of B-ALL characterized by a distinct transcriptional signature and frequent PAX5 fusions (PAX5-r). While PAX5-alt ALL has been associated with intermediate outcomes, clinical data specifically investigating pediatric PAX5-r ALL remain limited. We collected and analyzed 159 pediatric cases of PAX5-r ALL treated between 2001-2024 within AIEOP-BFM ALL studies across Italy, Germany and Austria, revealing high-risk clinical features. Comparative analyses of patients consecutively enrolled in the AIEOP-BFM ALL 2017 study (PAX5-r, n=96 vs. non-PAX5-r, n=1948) confirmed higher rates of hyperleukocytosis at diagnosis (22.9% vs. 8%, p<0.001) and enrichment of IKZF1plus profile (14.7% vs. 7.8%, p=0.0015) in PAX5-r patients. No relevant differences in terms of minimal/measurable residual disease (MRD)-based treatment response and risk-group stratification were observed. PAX5-r patients had a 4-year EFS and OS of 72.6±5.7% and 95.4±2.3%, respectively. Four-year EFS were 100%, 63.4±9.7% and 63.3±10% for standard-risk, medium-risk (MR) and high-risk (HR) groups, respectively, indicating that the poor prognostic impact of PAX5-r applies only when end-of-induction MRD is positive (MR/HR). Whole transcriptome sequencing revealed high FLT3 median expression in PAX5-r ALL and high-throughput drug screening of patient-derived xenografts (PDXs) showed marked sensitivity to several FLT3 inhibitors. Gilteritinib showed potent ex vivo cytotoxicity and synergism with dexamethasone in PAX5-r PDX models. Collectively, this study investigated clinical and biological features of pediatric PAX5-r ALL highlighting its MRD-dependent unfavorable prognosis and identifying FLT3 overexpression as a novel, potential therapeutic target.

Venous thromboembolism (VTE) provoked by transient risk factors is generally considered low risk, supporting short-term anticoagulation. However, this paradigm is based on heterogeneous definitions of provoking factors. In a prospective cohort study, we evaluated recurrence risk using the International Society on Thrombosis and Haemostasis (ISTH) classification of major and minor transient risk factors. Patients with symptomatic deep vein thrombosis and/or pulmonary embolism who completed ≥3 months of anticoagulation were followed after treatment discontinuation. Patients with cancer, major thrombophilia, pregnancy-associated VTE, or indication for extended anticoagulation were excluded. The primary outcome was symptomatic recurrent VTE. Cumulative incidence was estimated by Kaplan-Meier analysis. The study was terminated early due to unexpectedly high recurrence risk among patients with major provoking factors. Between 2019 and 2025, 242 patients were followed for a median of 23.9 months; 72 had major and 170 minor transient risk factors. Recurrent VTE occurred in 13 patients with major and 7 with minor risk factors. At 24 months, recurrence risk was 9.5% (95% CI, 6.0-14.0) overall, 19.7% (11.0-30.2) after major, and 5.0% (2.2-9.5) after minor risk factors. No recurrence occurred in 81 women with hormone-associated VTE; after their exclusion, the recurrence risk among patients with other minor risk factors increased to 9.1% (95% CI 4.0-17.0). Recurrence after provoked VTE is not uniformly low and varies substantially by the type of transient risk factor. These findings challenge current treatment paradigms and support individualized decisions regarding anticoagulation duration.

Pediatric central nervous system tumors remain a leading cause of cancer-related mortality in children, while their diagnosis, risk stratification, and therapeutic management increasingly depend on integrated molecular characterization. However, representative tumor tissue is often difficult to obtain because of tumor location, surgical risk, limited biopsy material, and the impracticality of repeated sampling during disease evolution. Cerebrospinal fluid (CSF) has therefore emerged as a particularly informative liquid biopsy compartment for many CNS malignancies, enriched in tumor-derived cell-free DNA and, for tumors in contact with the CSF spaces, more directly reflective of intracranial tumor biology than plasma; its yield nonetheless varies with tumor biology and anatomical proximity to CSF pathways. Here, we review the evidence supporting CSF cell-free DNA sequencing as an emerging extension of molecular neuropathology in pediatric CNS tumors. Targeted next-generation sequencing, low-pass whole-genome sequencing, methylation-based classifiers, and nanopore sequencing now enable complementary assessment of somatic mutations, copy number alterations, epigenetic tumor class, and longitudinal tumor burden from low-input pediatric CSF samples. Recent studies have moved the field beyond analytical proof of concept towards defined clinical scenarios, including molecular diagnosis when biopsy is infeasible, molecular staging of high-CSF-shedding tumors, minimal residual disease monitoring in medulloblastoma and other embryonal tumors, and clarification of ambiguous radiological progression. CSF-based sequencing does not replace tissue neuropathology, but provides a liquid molecular layer that can complement, extend, or in selected situations partially substitute tissue-based diagnosis. Its broader adoption now depends on workflow standardization, assay-specific reporting standards, external quality assurance, and prospective evidence that CSF-guided decisions improve patient outcomes.

Childhood scalp irradiation for tinea capitis (TC) increases the long-term risk of intracranial meningiomas. It remains unclear whether prior TC irradiation affects meningiomas' response to stereotactic radiosurgery (SRS). We compared TC-irradiated and sporadic meningiomas treated with SRS. Among 539 meningioma patients treated with SRS from 2010-2023, 204 met criteria for volumetric analysis (median follow-up 64.6 months, IQR 32.8-107.8). Of these, 61 (29.9%) had childhood scalp irradiation for TC, while 143 (70.1%) had no prior cranial irradiation. Tumor volumes were measured on T1-weighted gadolinium-enhanced MRI baseline and at last follow-up, or prior to surgery. Treatment response was assessed as percent volume change, as a binary study-defined "good response" (≥29% reduction), and RANO-aligned categories. Predictors of response and surgical intervention were evaluated using multivariable regression. TC-irradiated patients were older (median 67.6 vs. 62.8 years, P < .001) and more commonly had multiple meningiomas (73.8% vs. 11.9%, P < .001) than non-irradiated patients. Baseline tumor volume was similar between groups (P = .516), as was the need for surgical resection (P = .535). Multivariable analysis showed that TC irradiation independently predicted poorer volumetric response (a + 38.7% relative volume change, P = .026) and a lower likelihood of achieving the study-defined "good response," although this was not statistically significant. TC irradiation was not associated with progression-free survival. Childhood TC irradiation-related meningiomas are a distinct subgroup characterized by multifocality and reduced volumetric response to SRS. These findings suggest a potentially treatment-resistant phenotype, supporting the need for individualized management.

Vasu and colleagues report one of the first clinical evaluations of rapidly manufactured trispecific chimeric antigen receptor T cells targeting CD19, CD20, and CD22. The lymphoma efficacy signal and favorable observed safety profile support further investigation, whereas the correlative analyses suggest that baseline T-cell fitness and early post-infusion functional states may remain important determinants of outcome. See related article by Vasu et al., p. XX .

[This corrects the article DOI: 10.1002/hem3.70403.].

Artificial chemical synapses, which specifically identify, transmit, and process molecular information, find promising applications in precision medical diagnosis, neural-electronic interface, and in-memory computing. However, to implement biomarker-triggered neuronal excitability modulation with artificial iontronic devices remains a significant challenge. Herein, we demonstrate a capture DNA integrated angstrom-fluidic chemical synapse in which the intramembrane ionic conductance can be switched between excitatory and inhibitory states by specific DNA-target interactions on the outer membrane surface. Experimental results and theoretical calculations unveil that capture of specific biomarker results in a bidirectional space charge polarization, and establishes opposite local concentration gradient at the membrane surface. Driven by this reversible concentration gradient, cation influx or efflux modulate the number density of ionic charge carriers inside the membrane, analogy to the hyperpolarization and depolarization modes of biological chemical synapses. Using a convolutional neural network algorithm to process the ionic conductance enhancement and depletion signals, we develop a diagnostic approach for early prostate cancer with 100% accuracy for both retrospective analysis of 105 clinical specimens, and prospective double-blind trials (n = 10). This work sheds light on artificial chemical synapses based medical diagnosis, and provides a blueprint for neural-like iontronic network for chemical information processing.

Prostate-specific antigen (PSA) screening lacks specificity, particularly within the 4-10 ng/mL diagnostic gray zone, leading to unnecessary prostate biopsies and overtreatment. Here, we developed and validated a streamlined urine DNA methylation assay for non-invasive prostate cancer (PCa) detection and biopsy decision-making. Tissue-based Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq) was integrated with large-scale public methylome cohorts to identify PCa-specific hypermethylated regions. Candidate markers were further refined by targeted bisulfite sequencing (TBS) and translated into quantitative PCR (qPCR) assays using post-prostatic massage urine samples. In a retrospective development cohort of 348 participants, stepwise marker selection and logistic regression modelling generated a compact two-gene methylation assay comprising ADD3_2 and GSX2_2. The model was then evaluated in an independent prospective multicenter cohort of 200 participants. The assay achieved robust diagnostic performance, with areas under curve (AUC) of 0.86 in the development cohort and 0.91 in the validation cohort, while maintaining specificity above 90%. Performance was preserved in the PSA gray zone and for clinically significant PCa (csPCa). Decision curve analysis (DCA) indicated that integrating this tool could safely avert approximately 55% of unnecessary biopsies without compromising cancer detection. This simple qPCR-based two-gene urine methylation assay provides a scalable, cost-effective and non-invasive complement to PSA-based PCa screening.

Due to its high clinical and biological complexity, multiple myeloma (MM) is a malignancy of heterogeneous prognoses and outcomes. The International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) formulated a consensus genomic staging (CGS) of high-risk MM (HRMM), aiming to refine and homogenize the classification of high-risk disease. We evaluated the new HRMM criteria in a cohort of 1209 consecutive newly diagnosed MM patients with complete CGS data (except TP53 mutations), treated in a single center with contemporary regimens, including triplets and quadruplets, between 2010 and 2024. Based on CGS criteria, 25.2% of our cohort's patients were classified as HRMM. High-risk status was associated with significantly inferior outcomes: median overall survival (OS) was 44 months for HRMM versus 93 months for standard-risk (SR) patients (hazard ratio [HR] 1.81; P < 0.001), corresponding to 5-year OS rates of 40% versus 61%. Similarly, median progression-free survival was 21.3 months for HRMM versus 36 months for SR (HR 1.64; P < 0.001). The presence of ≥2 high-risk features identified an ultra-high-risk group (4.4% of patients) with a threefold increased risk of death, compared to SR patients. CGS remained prognostic irrespective of renal dysfunction, stratifying patients with sCr > 1.2 mg/dL (HR 1.71; P < 0.001) and retained prognostic significance across different age groups, transplant eligibility, and treatment eras (pre- and post-2020). The IMS/IMWG CGS effectively stratified patients in a large cohort treated at a tertiary academic center, identifying a substantially high-risk population with poor outcomes despite modern therapies. This validation supports its deployment in clinical practice and research to enhance the precision of risk-adapted management.

Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.

Talquetamab is the first and only approved bispecific antibody targeting G protein-coupled receptor class C group 5 member D (GPRC5D) for treatment of relapsed/refractory multiple myeloma based on results from the phase 1/2 MonumenTAL-1 study. Here, we report efficacy and ongoing safety from MonumenTAL-1 with 3 years of follow-up. Patients naïve to T-cell redirection therapy (TCR) received talquetamab 0.4 mg/kg weekly (n=143) or 0.8 mg/kg every other week (n=154); a separate cohort received prior TCR (n=78, either talquetamab dose). Median follow-up was 38, 31, and 30 months in the 3 cohorts, respectively, as of September 2024. Overall response rate was 67-74% and complete response or better rate was 33-42%. Median progression-free survival was 7.5, 11.2, and 7.7 months, and median overall survival (OS) was 34.0 months, not reached, and 28.3 months (36-month OS rates 49.3%, 60.8%, and 44.6%), in the 3 cohorts, respectively. The most common adverse events (AEs) were cytokine release syndrome (73-79%; grade 3/4, 0.6-2.1%), taste changes (72-76%), and infections (61-78%; grade 3/4, 21-26%). Ataxia/balance disorders occurred in 5.3% of patients (no grade 4/5 events). Dose reduction and discontinuation rates due to AEs remained low; no patients died due to talquetamab-related AEs. With 3 years of follow-up, talquetamab continued to demonstrate high rates of deep and durable responses. The long-term safety profile was comparable to previous results and continued to show lower risk of high-grade infections relative to approved BCMA-targeting bispecific antibodies. NCT03399799 (phase 1) and NCT04634552 (phase 2).

Computer-aided quality assurance (CAQ) can provide feedback to improve mucosal inspection during colonoscopy. This systematic review and meta-analysis of randomized controlled trials (RCTs) evaluated the efficacy of CAQ versus standard colonoscopy in enhancing colonoscopy quality indicators. Adhering to PRISMA guidelines, we searched MEDLINE, Embase, and CENTRAL for RCTs comparing CAQ with standard colonoscopy. The primary outcome was adenoma detection rate (ADR). Secondary outcomes included detection rates for advanced adenoma (AADR) and adenocarcinoma (ACDR), adenomas per colonoscopy (APC), and withdrawal time. Pooled risk ratios (RRs) and weighted mean differences (WMDs) were calculated using random-effects models. Six RCTs involving 5687 colonoscopies (CAQ 2895; standard colonoscopy 2792) were included. Compared with standard colonoscopy, CAQ increased ADR by 43% (RR [95%CI]: 1.43 [1.17-1.73]; P < 0.001, I2 = 73.5%), with heterogeneity decreasing substantially after omitting one study (1.52 [1.32-1.75]; P < 0.001, I2 = 11.9%); AADR by 54% (1.54 [1.26-1.87]; P < 0.001, I2 = 0.0%); ACDR by 30% (1.30 [1.00-1.68]; P = 0.047, I2 = 0.0%); APC by 0.14 adenomas (WMD [95%CI]: 0.14 [0.08-0.20]; P < 0.001, I2 = 53.2%); adenomas ≥10 mm by 0.03 adenomas (0.03 [0.02-0.05]; P < 0.001, I2 = 45.1%); and withdrawal time increased by 0.64 minutes (0.64 [0.04-1.24]; P = 0.04, I2 = 96.1%). CAQ significantly improved ADR and detection of clinically significant lesions. While findings for AADR and ACDR should be interpreted with caution due to low event rates, the improvements in detection of adenomas ≥10 mm and APC suggest that CAQ may lower the risk of post-colonoscopy colorectal cancer, a hypothesis that warrants evaluation in future long-term analyses of patient outcomes.

The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre-CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post-CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially those progressing after Bruton tyrosine kinase (BTK) inhibitor and/or chimeric antigen receptor (CAR) T-cell therapy and those with high-risk features, have poor outcomes. The bispecific antibody, mosunetuzumab, combined with the antibody-drug conjugate (ADC), polatuzumab vedotin (Mosun-Pola), targets CD20 and CD79b via independent cell-killing mechanisms. In this multicenter phase 2 study, patients with MCL who had received ≥2 previous lines of therapy, including a BTK inhibitor, were enrolled. Patients received outpatient fixed-duration mosunetuzumab subcutaneously (17 cycles), with cycle 1 step-up dosing to mitigate cytokine release syndrome (CRS), and polatuzumab vedotin (1.8 mg/kg IV) for 6 cycles. The primary end point was centrally assessed best objective response rate. A total of 42 patients with a median of 3 previous therapies were enrolled; 26% had previous CAR T-cell therapy. A number of patients had MCL with high-risk features (Ki-67 of ≥50%, 67%; blastoid/pleomorphic morphology, 38%; TP53 aberration, 48%). Objective response occurred in 88.1% of evaluable patients (95% confidence interval [CI], 74.4-96.0) and complete response in 78.6% (95% CI, 63.2-89.7). With a median follow-up of 15.9 months, median progression-free survival was 18.6 months (95% CI, 13.9 to not estimable). Consistent efficacy was observed in high-risk subgroups. CRS occurred in 42.9% of patients and was limited to grade 1/2 events. Mosun-Pola achieved high complete remission rates while maintaining a manageable safety profile in patients with R/R MCL exhibiting high-risk features. This is, to our knowledge, the first bispecific-ADC combination therapy study in MCL. This trial was registered at www.clinicaltrials.gov as #NCT03671018.

Bevacizumab is widely used as an anti-angiogenic maintenance therapy in ovarian cancer; however, there are currently no validated clinical criteria to guide patient selection for its use. To satisfy the urgent need for bevacizumab response biomarkers, we created a novel RNA-seq dataset (n = 244) and applied unsupervised and supervised machine learning to identify expression signatures associated with benefit from adding bevacizumab to standard treatment and validated our findings using a previously published microarray dataset (n = 377). Additionally, we validated the existence of the discovered signatures using RNA-seq data from the TCGA-OV cohort (n = 426) and performed public expression data mining to provide a biological interpretation of the prioritized signature. Among expression signatures reproducibly detected in independent datasets, one was prioritized as a potential predictive biomarker for bevacizumab benefit. Further stratified analysis revealed that over-expression of this signature was associated with improved overall survival in patients who received bevacizumab in addition to standard chemotherapy in both novel (HR = 0.41, 95% CI: (0.23-0.74), adj.p-value = 0.008) and previously published cohorts (HR = 0.51, 95% CI: (0.34-0.75), adj.p-value = 0.003), while no significant survival benefit from bevacizumab was observed in patients negative for this signature. We hypothesize that this signature may be associated with stemness-like features, possibly driven by CTCFL. In addition, we identified several other signatures reproducible in independent datasets and not related to known molecular subtypes of ovarian cancer, which may also represent biomarker candidates and require further validation in additional RNA-seq data. We identified a previously undescribed expression signature with potential predictive value for bevacizumab benefit, and revealed transcriptional heterogeneity of ovarian cancer that extends beyond current molecular classifications. Given the high heterogeneity of ovarian cancer and that the novel signature only partially explains variation in survival outcomes under bevacizumab treatment, larger RNA-seq datasets are required to further improve predictive models.

Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.

Innate immunity constitutes the body's first line of defense, deploying evolutionarily conserved mechanisms to detect and respond to pathogenic threats and tissue injury. In contrast to the adaptive immune system's specificity and memory, innate immunity relies on germline-encoded pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). This review outlines the major PRR families and their downstream signaling pathways, culminating in the production of cytokines and inflammasome activation. Additionally, this review explores the functional integration of cellular responses and examines the sophisticated regulatory circuits, including transcriptional, posttranscriptional, epigenetic, and metabolic mechanisms, that calibrate innate immune responses. Importantly, we highlight how dysregulated innate immunity underlies a wide spectrum of diseases, from autoinflammatory and autoimmune disorders to chronic inflammatory states and cancer. Recent insights into trained immunity and innate immune memory further redefine the scope of innate defenses, revealing that metabolic and epigenetic remodeling can prime innate cells for enhanced secondary responses. Finally, we discuss the therapeutic potential of modulating innate pathways, including PRR agonists as vaccine adjuvants or anticancer agents, and PRR inhibitors in autoimmune and inflammatory diseases. By integrating current mechanistic knowledge with emerging therapeutic strategies, this review underscores the central role of innate immunity in health and disease while pointing toward promising avenues for future research and clinical translation.

Platelets have been increasingly recognized as versatile regulators of ageing, immunity, and cancer, yet their functional heterogeneity has remained poorly defined. We performed the first large-scale single-cell RNA sequencing of 28,192 platelets from healthy, aged, metastatic, and treated mice using the BD Rhapsody platform. Our analysis revealed four conserved and functionally distinct platelet transcriptional states: haemostatic platelet (HP), neural gene-enriched platelet (NEP), platelet-leukocyte aggregate (PLA) and platelet-erythrocyte aggregate (PEA). Among these states, Tpm2-high HP is linked to ageing-associated lung metastasis and is characterized by cytoskeletal remodelling gene signatures. The PLA state was predicted to be a signalling hub for immunothrombosis, with a PLA-Bridge subpopulation coordinating immune-adherent platelets via the Ppbp-Cxcl2 and Thbs1-Cd47 checkpoint axes. Strikingly, AAV-mPf4 gene therapy was associated with a neural gene-enriched platelet-associated transcriptional program, which mitigates age-related functional decline. This study provides a single-cell transcriptomic atlas of murine platelets under ageing and metastasis conditions and reveals transcriptional state-specific heterogeneity. This study also proposes PF4-based interventions and cytoskeletal candidates for diagnosis and therapy.

The Tn antigen, a truncated O-glycan, is frequently elevated in pancreatic ductal adenocarcinoma (PDAC). Multiple therapeutic approaches targeting Tn have been developed, but they have not demonstrated clear efficacy signals in early phase clinical studies. Improving Tn-targeted strategies in PDAC will require both overcoming the immunosuppressive tumor microenvironment and defining pathways by which truncated O-glycans promote growth and immune evasion. Here, we showed that Tn reshapes the tumor immune landscape of PDAC. Expression of Tn antigen on PDAC cells enhanced proliferation in vitro and tumor growth in vivo. Tn expression remodeled the immune microenvironment, skewing tumor-associated macrophages toward M2-like phenotypes, reducing cross-presenting dendritic cells, and expanding myeloid-derived suppressor cells (MDSCs). Single-cell RNA sequencing confirmed expansion of MDSCs and downregulation of antigen processing and presentation in the immune cell infiltrate of Tn+ tumors. Tumor-intrinsic transcriptomic analyses revealed activation of TNF-α/NF-κB signaling and induction of IL-34, a cytokine linked to monocyte survival and differentiation in Tn antigen expressing tumors. Additionally, high Tn expression in both organoids derived from pancreatic cancer patients and in PDAC mouse models was associated with increased IL-34 expression. Genetic deletion of Il34 in PDAC cells attenuated Tn-driven tumorigenesis and reduced MDSC infiltration, while recombinant IL-34 promoted myeloid cell differentiation and proliferation in vitro. Together, these findings establish a glyco-immune-cytokine axis in which truncated O-glycans contribute to IL-34-mediated immunosuppression, providing mechanistic insight and potential therapeutic targets in PDAC.

Recent advances have demonstrated the application of microcavity-containing hydrogel microparticles, known as nanovials, for massively parallel and high-throughput screening of therapeutic T cell populations for adoptive cell therapies. Nanovial cavities coated with peptide-MHC (pMHC) or antigen tetramers selectively bind to their cognate T cell receptor (TCR) or chimeric antigen receptor (CAR) to activate T cells and capture secreted cytokines. However, binding of tetramers or recombinantly expressed antigen by T cells may not reflect physiological T cell activation or cytotoxicity, as the binding interface is not fully representative of the natural immunological synapse formed between T cells and professional antigen-presenting cells (APCs). Here, we leverage the recent discovery of an ESCRT- and ALIX-binding region (EABR) sequence to generate antigen-presenting vesicles and cancer-mimicking exosomes from standard HEK293T and Expi293F cell cultures. EABR-mediated vesicles present natural, full-length oncologically relevant membrane proteins embedded in lipid bilayers to functionalize the nanovial cavity with cell-like membranes. Hydrogel nanovials functionalized with the EABR-mediated vesicles show improved T cell capture of 1G4 T cells and enhanced induction of secretion in HER2 CAR-T cells compared to hydrogel surfaces functionalized with recombinantly expressed soluble proteins.

The liver-secreted protein fibrinogen-like protein 1 (FGL1) is a ligand of the coinhibitory receptor LAG3 on T cells; however, Fgl1-/- mice exhibit autoimmune features distinct from those of Lag3-/- mice. Here, we examined whether FGL1 acts via receptors beyond LAG3 to regulate autoimmunity. Recombinant FGL1 administration reduced autoimmune symptoms in B6/lpr lupus-like mice. This was associated with diminished antigen-specific IgM responses and B cell numbers. Genome-wide surface proteome screening identified the tumor necrosis factor receptor (TNFR) family member transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a receptor for B cell-activating receptors BAFF and APRIL, as a receptor for FGL1. TACI bound FGL1 via an N-terminal site not required for BAFF and APRIL interaction. The impact of FGL1 administration on B cell numbers and autoimmune phenotypes was lost in Taci-/- mice. Mechanistically, FGL1 promotes TACI internalization, thereby regulating receptor availability for activating ligands. Thus, FGL1 regulates an innate-like subset of B cells via modulating TACI availability, with implications for autoimmunity and inflammation.

Metastatic microenvironments vary widely not only in their biochemical composition but also in their mechanical properties. Here, we examined how the mechanical rigidity of the metastatic niche affects metastases seeding and the local efficacy of antitumor immunosurveillance. Cancer cells stiffened in response to increasing environmental rigidity, a biophysical change that mechanically sensitized them to killing by cytotoxic lymphocytes. In immunodeficient mice, rigidity sensing by cancer cells yielded robust bone colonization, accompanied by marked stiffening of the cancer cells themselves. Conversely, in immunocompetent hosts, stiffer cancer cells were selectively eliminated, and bone metastasis was suppressed. In patients, metastatic cell stiffness was associated directly with environmental rigidity and inversely with immune infiltration. Expression of Spp1, encoding the secreted glycoprotein osteopontin, defined a subset of cancer cells that expanded in the bone, and deletion of Spp1 limited environmentally induced cancer cell stiffening, bone colonization, and immune vulnerability. Thus, environmental mechanosensing regulates both metastases seeding and antitumor immunity, providing an immunological basis for metastatic site selection.

Clinical translation of nanomedicines remains constrained by a persistent gap between static preclinical assays and the dynamic shear environment of the human vasculature. This review argues that fluid shear stress is an underappreciated contributor to clinical attrition, acting alongside well-established factors including biomarker-target mismatch, enhanced permeability and retention heterogeneity, preclinical-clinical discordance in tumor biology, and manufacturing variability. Circulating nanocarriers traverse a mechanical environment in which wall shear stress spans from 0.1 dyn/cm2 in hepatic sinusoids to over 1000 dyn/cm2 in stenotic regions. Emerging quantitative studies indicate that these forces can modulate carrier stability, protein-corona composition, and drug release in ways that static in vitro assays cannot resolve, with the cholesterol-rigidified bilayer of Doxil and the shear-activated platforms of Korin and colleagues providing representative positive control and mechanistic evidence. We synthesize recent progress at the interface of computational fluid dynamics and machine learning. Physics-informed neural networks, deep operator networks, and graph neural networks feature prominently in this synthesis and underpin an integrated framework for mechanistically informed pharmacokinetic prediction. Reported benchmarks show surrogate models reconstructing hemodynamic fields with under 5% error relative to high-fidelity CFD while reducing data requirements 5- to 10-fold, and convolutional surrogates trained on approximately 1800 patient-specific simulations predicting time-averaged wall shear stress with 2.5% mean absolute error. These surrogate models integrate hemodynamic descriptors (TAWSS, OSI, and RRT) with distributional particle features (D10, D50, and D90). We outline the evidentiary and methodological path toward biomechanically informed nanomedicine development aligned with emerging regulatory frameworks, while acknowledging that routine regulatory acceptance of computational shear modeling remains a future milestone rather than current practice.

Clinical translation of nanomedicines is greatly hindered by insufficient understanding of their in vivo process, yet a key challenge lies in quantifying the encapsulated versus free drug forms in tissues and cells. Herein, we present a facile, versatile anti-PEG single-chain variable-fragment antibody (PEG-scFv)-based method enabling quantitative measurement of both forms in various biofluids (e.g., interstitial fluid, cytoplasm). By this method, we map the in vivo process of PEGylated liposomal doxorubicin (sLip/Dox) at unprecedented resolution. In the bloodstream, doxorubicin remains largely encapsulated in liposomes (>99%). In liver as the main organ for drug elimination, less drug was distributed in the interstitium (>80% encapsulated) but more in liver cells (mainly in Kupffer cells) released in a time-dependent manner, accompanying doxorubicin transferred to hepatocytes most in free form by 12 h postinjection. After extravasation into tumors, there was a limited access of sLip/Dox to tumor cells, confining most of the drug in the interstitium mainly being encapsulated (more than 75%), and the internalized fraction underwent a gradual release process in both tumor-associated macrophages and tumor cells. These findings revealed that for sLip/Dox, which primarily underwent drug release intracellularly, cellular internalization rates could be the key factor in determining its in vivo performance. Given widespread PEGylation on developing nanomedicines and the cost-effectiveness of scFv production, PEG-scFv offers a broadly applicable tool for dissecting in vivo processes of nanomedicines to establish dose-effect relationships like small-molecule drugs, further to guide rational nanotherapeutic design.

CX-5461 (pidnarulex) is the most clinically advanced small-molecule ligand associated with G-quadruplex (G4) targeting and shows activity in DNA repair-deficient tumors, yet its clinical use is associated with dose-limiting phototoxicity. Here, we repurpose this intrinsic photoreactivity to investigate CX-5461 as a G4-associated, light-activated antitumor scaffold. In solution, CX-5461 produces both Type I and Type II reactive oxygen species (ROS), whereas complexation with G4 DNA markedly decreases detectable singlet oxygen (1O2) formation and favors radical-associated Type I oxidation. This G4-modulated photochemical shift drives oxidative remodeling and destabilization of G4-containing DNA. In cancer cells, photoactivation enhances cytotoxicity by up to two orders of magnitude relative to the dark state and is accompanied by elevated intracellular ROS, increased 8-oxoG formation, γ-H2AX accumulation, and changes in BG4-detected nuclear G4 structures. In vivo, light-activated CX-5461 suppresses tumor growth and extends survival in immunocompetent syngeneic models, eliciting hallmarks consistent with immunogenic genome stress. Collectively, these findings reposition CX-5461 as a clinically relevant scaffold for G4-associated photogenomic cancer therapy, while supporting a model in which broader oxidative DNA damage may also contribute to the biological response.

CpG dinucleotides are mutational hotspots due to spontaneous deamination of 5-methylcytosine (5mC), resulting in T:G mismatches that can lead to CpG>TpG transitions. These mutations are a hallmark of aging and cancer and play a central role in the evolution of vertebrate genomes. We have previously uncovered MBD4 as the primary base excision repair (BER) glycosylase responsible for 5mC deamination repair. Here, we employ an APOBEC1 deaminase fused to a catalytically dead Cas9 to induce targeted 5mC deamination independently of DNA replication and track its repair in human cells. This approach reveals that MBD4 elicits a coordinated repair response with a non-canonical branch of mismatch repair (MMR) involving complexes MutLβ (MLH1-PMS1) and MutSα (MSH2-MSH6). We uncover the physical interaction between MBD4 and MutLβ and demonstrate that MBD4-mediated repair requires MLH1. We show that PMS1 deficiency phenocopies the CpG>TpG hypermutation signature characteristic of MBD4 loss, establishing 5mC deamination repair as a key function of human PMS1. In alignment with our experimental data, we show that the CpG>TpG mutational burden in MMR-deficient tumors is partly explained by replication-independent processes. Altogether, we uncover a novel function of non-canonical MMR that underscores its interplay with BER in safeguarding genomic integrity against damage to methylated DNA.

The BCL-2 inhibitor venetoclax has transformed outcomes for older or frail patients with acute myeloid leukemia (AML), and its resistance mechanisms are becoming better defined, including compensatory and lineage-associated switches toward MCL-1 or BCL-xL dependence, oncogenic signaling activation, blast phenotype, and differentiation stage. Additional putative mechanisms-such as emerging BAX mutations, mitochondrial structure remodeling, integrated stress response, and metabolic adaptations, including enhanced amino acid uptake and fatty acid oxidation to sustain oxidative phosphorylation-require further validation.

Diffuse hemispheric glioma (DHG), H3 G34-mutant, is a highly aggressive and fatal pediatric brain tumor, with a median survival of only ∼18 months and no effective targeted therapies. While CAR T cell therapy has shown success in B-cell leukemia and promise in other pediatric CNS tumors, it has not yet been evaluated explicitly in preclinical or clinical models of DHG. B7-H3 (CD276), a tumor-associated antigen overexpressed in pediatric brain tumors, represents a promising target for immunotherapeutic intervention in DHG. Here, we present the first preclinical evaluation of B7-H3-directed CAR T cell therapy in DHG. We evaluated B7-H3 expression in specimens from DHG patients and patient-derived cell lines. Two B7-H3-targeted CAR constructs were generated and evaluated for antigen-specific activation, cytokine production, exhaustion, and cytotoxicity in vitro. Therapeutic efficacy was assessed in multiple orthotopic DHG xenograft models, followed by multiplex immunofluorescence and serum cytokine profiling. B7-H3 was highly expressed in DHG tumors and cell lines, but at minimal levels in normal brain tissue. B7-H3 CAR T cells demonstrated potent, antigen-specific cytotoxicity against DHG cells, with negligible activity against B7-H3-knockout DHG cells. In vivo, the intratumoral administration of B7-H3 CAR T cells led to significant tumor regression and a substantial extension of survival in three DHG mouse models, with durable tumor eradication. This study provides preclinical evidence supporting B7-H3 CAR T cell therapy as a highly effective immunotherapeutic strategy for DHG. Our findings support B7-H3 as a compelling immunotherapeutic target for DHG, laying the groundwork for clinical translation.

In this issue of Blood Cancer Discovery, Yang and colleagues present a comprehensive repository of patient-derived xenograft models of aggressive large B-cell lymphoma. The publicly available resource links disease specimens from individuals treated with diverse modern therapies (including chimeric antigen receptor T cells) to their high-risk clinical treatment histories and the molecular and transcriptional characteristics of their tumors, enabling the study of tumor cell-intrinsic mechanisms of therapeutic resistance and susceptibility to novel therapies. See related article by Yang et al., p. XX .

Antibiotics compromise the efficacy of immune checkpoint inhibition (ICI) therapy in cancer, but the underlying mechanism remains unclear. In this issue of Cancer Cell, Mallard de La Varende et al. identify dysbiosis-associated tauro-conjugated bile acids as drivers of ICI non-response and γ-glutamyl transferase (γGT) as a predictive biomarker.

Menin inhibition, an approved therapy for KMT2A-rearranged and NPM1 mutant acute leukemia, is accompanied by decreased platelet counts in 15-20% of heavily pre-treated patients. While studying the mechanism underlying this effect, we discovered that menin inhibition reduced the numbers of megakaryocyte progenitors in human CD34+ cultures and in mice. Because megakaryocytes are key drivers of myeloproliferative neoplasms (MPNs), we investigated the extent to which menin inhibition ameliorates MPN phenotypes. We found that the menin inhibitor revumenib has potent anti-tumor activity, synergizes with ruxolitinib, and shows only subtle effects on healthy mice. Moreover, revumenib suppressed megakaryopoiesis of primary MPN patient specimens in vitro and in vivo. Importantly, genetic knockout of MEN1 and its target MEF2C phenocopied the action of revumenib, confirming an on-target effect of the drug. Together, we reveal menin as a dependency in proliferative megakaryocytes and support further evaluation of menin inhibition as a potential therapy for MPNs.

In this issue of Cancer Cell, Liang et al. report PathPrism, demonstrating how interpretable spatial representations of tissue organization can support biomarker discovery, clinical prediction, and hypothesis generation from routine histopathology slides. The framework highlights an emerging transition in computational pathology from black-box prediction toward biologically meaningful interpretation.

Cranial radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ; Stupp protocol) prolongs glioma survival but frequently results in persistent cognitive impairment. Human neural stem cell (hNSC)-derived extracellular vesicles (EVs) are a promising acellular therapy whose bioactive cargo can modulate neuroinflammation and synaptic integrity. We evaluated two EVs derived from GMP-grade hNSCs (Shef6 and UCI-191) in syngeneic glioma-bearing and non-tumor adult mice treated with fractionated cranial RT (3 × 8.67 Gy) together with concomitant low-dose (25 mg/kg) and adjuvant high-dose (66.7 mg/kg, intraperitoneal) TMZ. EV administration improved memory performance in RT-TMZ-exposed mice and, notably, Shef6-EVs also extended survival in glioma-bearing mice in the absence of chemoradiotherapy. Immunofluorescence analyses demonstrated attenuated gliosis and preservation of synaptic integrity in EV-treated RT-TMZ-exposed brains, while transcriptomic profiling identified distinct neuroprotective gene expression pathways associated with each EV source. Critically, neither Shef6 nor UCI-191 EVs diminished or interfered with the anti-tumor efficacy of RT-TMZ. These data support hNSC-derived EVs as a translational strategy to mitigate treatment-related neurotoxicity while preserving oncologic benefit in a clinically relevant glioma model.

Monoclonal gammopathy of undetermined significance (MGUS), monoclonal B-cell lymphocytosis (MBL), and clonal hematopoiesis (CH) of indeterminate potential represent highly prevalent, age-associated precursor states characterized by detectable serological, cellular, or genetic alterations in otherwise asymptomatic individuals. The advent of high-sensitivity technologies, including mass spectrometry, multiparametric flow cytometry, and next-generation sequencing, has revealed that these conditions are far more widespread than previously appreciated, yet only a minority of affected individuals progress to overt malignancies such as multiple myeloma, chronic lymphocytic leukemia, or myeloid neoplasms. Across these entities, a unifying paradigm is emerging in which malignant transformation is governed not simply by the presence of driver lesions, but by dynamic clonal evolution shaped by intrinsic fitness, temporal acquisition of alterations, and selective pressures imposed by the aging microenvironment. In CH, mutation-specific growth kinetics and inflammation-driven selection define both hematologic and systemic risks. In MBL, antigenic stimulation, immune dysfunction, and genetic complexity modulate progression to CLL. In MGUS, disease evolution reflects a gradual co-evolution between plasma cell clones and a progressively permissive niche. Aging-associated inflammation and tissue remodeling act as common denominators, fostering a competitive landscape that selectively advantages aberrant clones while suppressing normal hematopoiesis. In turn, these clones actively remodel their microenvironment, establishing feed-forward loops that sustain clonal expansion and malignant potential. Integrating insights across CH, MBL, and MGUS highlights shared biological principles and supports a shift toward "precision prevention" strategies aimed at intercepting high-risk trajectories while minimizing unnecessary surveillance in low-risk individuals.

Selective therapeutic gene activation in tumors remains challenging because tumor-enriched promoters often exhibit basal activity in non-target cells and may not fully capture intratumoral heterogeneity. In addition, direct promoter-driven expression of cytotoxic or tumor-suppressive payloads may be vulnerable to promoter leakiness, which can compromise specificity and safety. Here, we developed SLICER, a two-vector adeno-associated virus (AAV)-delivered Cre-loxP gene circuit that integrates an alpha-fetoprotein (AFP) promoter-driven sensor with post-transcriptional gating through microRNA (miRNA) recognition elements (MREs) for miR-21 and miR-122. This dual-layer design separates tumor-context sensing from downstream payload activation, converting context-dependent Cre accumulation into recombination-gated payload expression from the actuator vector. In AFP-active liver tumor cell models, including HepG2, Huh7, and PLC/PRF/5, SLICER induced robust Cre expression and loxP-dependent luciferase activation, whereas non-target/comparator cells showed minimal background activity and limited functional toxicity. Mutation of miR-21 and/or miR-122 recognition elements increased Cre accumulation and reporter output, supporting an MRE-dependent gating mechanism that contributes to circuit specificity. A pro-apoptotic BAX payload triggered caspase-dependent apoptosis in target cells, which was partially attenuated by Z-VAD-FMK, while non-target cells remained largely unaffected. Perturbation of miRNA inputs further tuned circuit output, consistent with miRNA-guided regulation. SLICER also accommodated modular tumor-suppressor payloads, including TP53 and PTEN, supporting actuator-layer interchangeability. In vivo, systemic AAV delivery of SLICER-TP53 suppressed tumor growth and reduced tumor burden in both HepG2 and Huh7 xenograft models, accompanied by increased intratumoral P53 expression. Together, these findings establish SLICER as a modular proof-of-concept platform for combinatorial transcriptional and post-transcriptional control of therapeutic gene activation in AFP-active liver tumor contexts, while supporting further development of logic-gated gene circuits for more precise tumor-selective payload delivery.

Cancer and cardiovascular diseases, the primary causes of mortality globally, are increasingly understood as biologically interconnected rather than distinct pathologies. Recent evidence indicates that protein homeostasis (proteostasis) functions as a crucial molecular link connecting tumor progression, therapeutic resistance, cardiac remodeling, and treatment-related cardiotoxicity. Proteostasis, which encompasses the cellular processes of protein synthesis, folding, quality control, and degradation, dictates tissue adaptation to chronic stress. Notably, the adaptive mechanisms that allow tumor cells to endure proteotoxic stress and resist therapy are often vital for maintaining cardiac structure and function. Thus, tumor control and cardiovascular injury may be divergent outcomes of a common stress-response framework. In this review, we propose proteostasis as a comprehensive framework for understanding the cancer-cardiovascular interface. We analyze how the ubiquitin-proteasome system, autophagy-lysosome pathway, endoplasmic reticulum stress-induced unfolded protein response signaling, and molecular chaperone networks are differentially reconfigured in cancer and cardiac tissues, influencing tumor survival, therapeutic susceptibility, and cardiovascular dysfunction. Additionally, we explore the translational implications of proteostasis dysregulation, including mechanisms of anticancer therapy-induced cardiotoxicity, emerging biomarkers, cardioprotective strategies, and opportunities for precision cardio-oncology. By conceptualizing efficacy and toxicity as interconnected outcomes of shared proteostasis biology, this review establishes a foundation for developing therapies that optimize cancer control while safeguarding cardiovascular health.

Organoids are powerful models for developmental biology, disease modelling, and personalized medicine. However, their broader application is limited by the inability of extracellular matrix (ECM) hydrogels to mimic the biomechanical and biochemical properties of native tissues. Dependence on poorly-defined basement membrane matrices such as Matrigel-a xenogenic, tumor-derived, nontunable material-introduces organoid growth variability and constrains reproducibility across organoid systems. In this study, we report a fully defined ECM platform that integrates key biomechanical and biochemical features of native tissue to support organoid growth. Using gelatin methacryloyl (GelMA) as a tunable hydrogel backbone, supplemented with laminin-entactin complex, we established a matrix with physiologically relevant stiffness and biochemical composition for mouse small intestinal organoids (mSIOs). The optimized matrix (2% w/v DS95 GelMA with 2 mg mL- 1 laminin-entactin) supported robust mSIO proliferation, morphology, and differentiation comparable to or exceeding that achieved with Matrigel. Importantly, continuous passaging was achieved without affecting organoid quality, suggesting feasibility of long-term mSIO expansion. These findings demonstrate that coordinated control of matrix mechanics and biochemical cues is critical for organoid development. The simplicity, stability, and tunability of this GelMA-based system provides a scalable and reproducible alternative to Matrigel, with broad potential for organoid culture, mechanistic studies, and translational applications.

Healthcare artificial intelligence systems often degrade in performance when deployed across institutions, with documented performance drops and perpetuation of discriminatory patterns embedded in data. This brittleness comes, in part, from learning statistical associations rather than causal mechanisms. Causal graph neural networks address this by combining graph-based representations of biomedical data with causal inference to learn invariant mechanisms instead of just spurious correlations. This Perspective reviews the methodology of structural causal models, disentangled causal representation learning, and techniques for interventional prediction and counterfactual reasoning on graphs. We discuss applications across psychiatric diagnosis and brain network analysis, cancer subtyping with multi-omics causal integration, continuous physiological monitoring and drug recommendations. These methods provide building blocks for patient-specific causal digital twins that could support in silico clinical experimentation. Remaining challenges include computational costs that preclude real-time deployment, validation challenges that go beyond standard cross-validation, and the risk of causal-washing where methods adopt causal terminology without rigorous evidentiary support. We propose a tiered framework distinguishing causally inspired architectures from causally validated discoveries and outline future directions, including scalable causal discovery, multimodal data integration and regulatory pathways for these methods. Making practical causal digital twins possible will require an honest assessment of what current methods deliver, sustained collaboration across disciplines and validation standards that match the strength of the causal claims being made.

Intratumor heterogeneity poses a fundamental challenge across the cancer care continuum, from diagnosis to treatment resistance and metastasis. Over recent decades, multiregion and multiomic profiling of tissue, together with functional studies and longitudinal plasma sampling, have revealed the dynamic and multidimensional evolution of tumor ecosystems. This complexity spans genetic and non-genetic mechanisms within cancer cells and their microenvironment. In this Review, we synthesize the current understanding of heterogeneity and evolution and discuss how these insights can inform the development of evolution-aware diagnostic and therapeutic strategies.

Inflammation is a fundamental immune response that protects against injury and infection; however, when unresolved, it can contribute to disease pathogenesis. Chronic inflammation is a hallmark of cancer that promotes tumour initiation and metastatic spread. Notably, this relationship is bidirectional: while chronic inflammation can promote tumour initiation, tumours themselves actively drive systemic inflammation. Two related members of the interleukin-1 (IL-1) family, IL-1α and IL-1β, are pleiotropic cytokines that link local tumour activity to systemic immune dysregulation and have emerged as principal drivers of this process. Tumour-derived IL-1β reshapes haematopoiesis in the bone marrow, promoting myeloid-skewed output and the expansion and polarisation of monocytes and neutrophils. These tumour-educated myeloid cells actively contribute to disease progression and metastatic spread through a range of mechanisms including suppression of anti-tumour immunity. In this review, we synthesise the current understanding of how tumours induce IL-1 production and how IL-1-driven systemic inflammation remodels the tumour macro-environment. We highlight emerging evidence that myeloid cell reprogramming occurs in a layered process, proposing a model of hierarchical myeloid education across the bone marrow and peripheral tissues and outline the therapeutic potential of targeting IL-1 signalling to disrupt tumour-promoting inflammation.

The molecular mechanisms by which KMT2A-rearranged (KMT2A-r) leukemias maintain the oncogenic FLT3 expression remain largely unclear, limiting therapeutic opportunities. Here, we identify the RNA binding protein MBNL1 as an unexpected positive regulator of FLT3 by DepMap dataset exploration and combinatorial CRISPR screens. MBNL1 promotes leukemia cell survival in cell lines and primary tumors by sustaining FLT3 expression in a KMT2A-r context-dependent manner. Mechanistically, we discover that MBNL1 recognizes a structured single-stranded DNA (ssDNA) element containing five consecutive guanines within the FLT3 enhancer, through MBNL1's zinc finger domains and the carboxyl-terminal unstructured region. Such MBNL1 protein/ssDNA interaction was evident in KMT2A-r leukemia using ChIP-seq and KAS-seq. Mutations of key amino acids of MBNL1's ssDNA binding surface or the critical guanines in ssDNA markedly abrogate the protein-ssDNA interactions. These findings implicate MBNL1 as a distinct FLT3 activator by recognizing a structured enhancer ssDNA element, highlighting an unexpected role for RNA binding proteins in transcriptional regulation through direct ssDNA recognition.

Capsid stabilization, induced by low-nanomolar concentrations of Lenacapavir (LEN)-a first-in-class capsid inhibitor-impedes HIV-1 replication in macrophages without disrupting reverse transcription or nuclear import. In LEN-treated cells, ultrastructural analyses reveal preserved conical capsids persisting within nuclear CPSF6-enriched puncta-HIV-1-induced membraneless organelles (HIV-1-MLOs)-which remain spatially segregated from canonical integration hubs near nuclear speckles (NSs). Rather than fusing with NSs, HIV-1-MLOs are rerouted to chromatin-associated promyelocytic leukemia nuclear bodies (PML-NBs), where molecular exchange occurs without condensate fusion. This nuclear redirection correlates with the sequestration of the viral genome within stabilized capsids, reducing the pool of viral DNA available for integration and redirecting the few accessible genomes to atypical integration sites near PML-NBs. These findings uncover a previously unrecognized mechanism of LEN action, whereby capsid stabilization reprograms the nuclear fate of the HIV-1 genome in macrophages, limiting integration and redirecting viral DNA toward more repressive nuclear environments, likely shaping the transcriptional potential of newly integrated viral DNA.

Conventional receptor-targeted fluorescent probes have shown promise in tumor imaging, yet achieving a high tumor-to-normal (T/N) tissue ratio in vivo remains challenging due to limited biomarker density on tumor cell membranes. Here, we present an in situ assembly strategy of bioorthogonal-functionalized chimeric artificial receptors (BCARs) that locally constructs BCARs on tumor surfaces, which amplify fluorescence signals and enable high-contrast imaging. Rapid, selective membrane engineering under physiological conditions increases effective receptor density, enhancing fluorophore binding and tumor visualization. Mechanistic studies reveal that BCARs exhibit exceptional membrane retention and spatial precision, sustaining signal amplification in heterogeneous tumor microenvironments. In air-pouch and orthotopic bladder cancer models, BCARs notably improve the T/N imaging ratio and tumor boundary delineation. Translational validation with surgical specimens from 14 patients with bladder cancer confirms clinical feasibility. This work establishes a versatile platform for on-site receptor reprogramming and signal amplification, offering a powerful tool for high-contrast tumor margin detection.

Down syndrome (DS) confers a developmentally rooted predisposition to both myeloid and lymphoid leukemias, particularly myeloid leukemia associated with DS (ML-DS) and acute lymphoblastic leukemia associated with DS (ALL-DS). While trisomy 21-driven gene dosage imbalance is central to this risk, DS leukemogenesis cannot be fully explained by recurrent mutations alone; it reflects a dynamic interplay between altered hematopoietic development, cell-intrinsic programs, and tissue microenvironmental cues. In this perspective, we argue that the field should move beyond cataloging cellular heterogeneity and adopt a topographic, multi-omic framework of DS leukemogenesis. We discuss how fetal niche biology shapes pre-leukemic evolution in ML-DS, including the developmental context of GATA1-mutant clones, and how therapy-driven bottlenecks may promote persistence of spatially protected residual disease in ALL-DS. We further highlight the translational potential of integrating spatially resolved transcriptomics with single-cell and protein-aware multi-omics to identify compartment-specific signaling programs and clinically actionable vulnerabilities. A spatially informed model of DS leukemia may improve biological stratification, clarify mechanisms of relapse and toxicity, and support the development of more effective and less toxic therapeutic strategies.

Early-stage mycosis fungoides (MF) often presents diagnostic challenges because of its clinical overlap with atopic dermatitis (AD). In clinical practice, we encountered a subset of patients with severe AD who fulfilled the MF diagnostic criteria yet remained clinically indistinguishable from AD and presented refractoriness to advanced therapies. We termed this ambiguous entity "mycosis fungoides-like AD" (mfAD) and sought to determine whether it represents malignant transformation or a distinct inflammatory endotype of AD. Skin biopsies were obtained from 7 patients with AD and 11 patients with mfAD. We performed paired single-cell RNA sequencing and single-cell T-cell receptor sequencing analyses. Publicly available MF and AD datasets were integrated for comparative analysis. Spatial transcriptomic profiling was used to contextualize single-cell findings within the tissue architecture. Comparative transcriptomic analysis revealed that T cells in mfAD were aligned with those in AD and lacked genomic instability. High-resolution profiling showed that mfAD was characterized by oligoclonal Th22 expansion rather than a single dominant malignant clone. Notably, all patients with mfAD achieved rapid clinical remission with selective JAK1 inhibition, indicating the therapeutic response characteristics of inflammatory dermatoses. Our findings demonstrate that mfAD is not a true malignancy, but rather a Th22-driven inflammatory endotype of AD. These results redefine mfAD as an inflammatory subtype within the AD spectrum, providing a mechanistic explanation for both the "pseudo-monoclonality" that leads to MF misdiagnosis and the failure of dupilumab. This study establishes a rationale for the use of JAK inhibitors in precision medicine for this patient population.

Speckle-type POZ protein (SPOP), a substrate receptor for the Cullin-3-RING (CRL3) ubiquitin ligase, is mutated in different cancers. Both activating and inactivating mutations in SPOP drive oncogenesis, underscoring the need for precise regulation. Among substrate receptors, SPOP uniquely assembles into filaments that are multivalent for substrate binding. Conversely, many substrates contain multiple SPOP-binding motifs. How this unusual reciprocal multivalent architecture regulates ubiquitination and how mutations activate SPOP are unclear. Gain-of-function mechanisms are also generally poorly understood. Here, we reveal that SPOP assemblies exist in an equilibrium between an active filament and a large, autoinhibited, circular "double-donut" state. Activating mutations shift the equilibrium, resulting in aberrant substrate turnover. Combinations of activating and inactivating mutations can produce intermediate activities, thus uncovering a tunable regulatory axis with implications for targeted cancer therapies. Therefore, SPOP's ability to assemble into long filaments is required for its regulation in human cells and underlies a gain-of-function mechanism.

Chimeric antigen receptor (CAR) T cell therapy faces challenges, such as tumor relapse due to antigen loss and poor CAR T cell expansion in vivo. Optimal tonic signaling (spontaneous CAR signaling) is crucial for CAR T cell fitness and antitumor function, requiring precise calibration to avoid dysfunction or exhaustion. Although CAR phase separation can enhance CAR clustering and tonic signaling to improve cytotoxicity and antigen sensitivity, constitutively high signaling could lead to potential side effects, including cytokine storm and neuronal toxicity. To overcome this limitation, we developed a drug-inducible phase-separation CAR (iPhase-CAR) system utilizing FDA-approved fulvestrant and an engineered estrogen receptor α (ERα) mutant as the drug-inducible phase-separation (DiPS) module. Incorporating the DiPS module into CARs enables drug-inducible clustering of CARs on T cell membranes. iPhase-CAR T cells demonstrate superior antitumor function. This system provides quantitative, reversible promotion of CAR T effector functions, enabling precise control over therapeutic efficacy only upon administration of the FDA-approved drug.

Synthetic lethality (SL) underlies the success of PARP1 inhibitors (PARPi) in treating homologous recombination (HR)-deficient cancers, yet their broader applicability beyond HR deficiency remains poorly defined. Here, we performed an in vivo CRISPR screen that identifies FANCA deficiency as a driver of tumor progression and PARPi SL, validated across diverse human cancer models. Notably, FANCA loss does not impair HR but instead disrupts FEN1 recruitment to replication forks, leading to defective Okazaki fragment maturation, lagging-strand single-strand DNA gap accumulation, and RPA exhaustion upon PARPi treatment. Additionally, FANCA loss in oncogene-expressing cells promotes transcription-replication conflict (TRC) accumulation selectively on the lagging strand and sensitizes HR-proficient cells to PARPi, a phenotype reversible by RNA polymerase II inhibition or RNase H overexpression. Together, these findings identify FANCA deficiency as a context-specific PARPi vulnerability and establish FANCA as a key suppressor of TRCs required for genomic stability under oncogenic replication stress.

Understanding how cells change state, interact with their neighbors, and organize into tissues requires recording of cellular lineage history in native spatial context. Here, we present SPACE-seq (spatial tracing enabled by CRISPR-based barcodes and slide-seq), a versatile platform that integrates CRISPR-based lineage recording with spatial transcriptomics to jointly resolve lineage, cell state, and tissue architecture at near-cellular resolution in situ. Using SPACE-seq, we uncovered intratumor transcriptional diversification among clonally related cells and identified tumor-stroma crosstalk that reciprocally reshapes behaviors of both malignant and stromal populations, which we further experimentally validated. Beyond disease, SPACE-seq revealed a narrow developmental window in which hepatoblast dispersion contributes to spatially confined lineage compartments that prefigure liver lobar architecture. Together, these results highlight the broad applicability and adaptability of SPACE-seq to uncover previously inaccessible principles of cellular organization, lineage dynamics, and tissue patterning.

Drug resistance is a major challenge in cancer therapy, especially in hematologic malignancies in which kinase inhibitors have transformed treatment yet are frequently undermined by drug resistance. Although targeted protein degradation (TPD) offers a mechanistically distinct mode of action compared with inhibition-based therapeutic therapies, the potential value of TPD in drug-resistant blood cancer remains unclear. Here, we report the discovery of cereblon (CRBN)-recruiting molecular glue degraders (MGDs) targeting lymphocyte-specific tyrosine kinase (LCK), an oncogenic kinase in T-cell acute lymphoblastic leukemia (T-ALL). By high-throughput screening and medicinal chemistry optimization, we developed a series of MGDs that induced CRBN-dependent degradation of LCK as well as potent cytotoxicity in T-ALL in vitro. Structure-activity relationship analysis and ternary complex modeling revealed a noncanonical degron at the LCK-CRBN interface involving the G-loop, whose mutation disrupts this interaction. Unlike inhibitors and inhibitor-based proteolysis-targeting chimeras, these MGDs engage LCK in regions distal to the ATP-binding site, and thus their activities in T-ALL are not affected by gatekeeper LCK mutations that drive resistance to inhibitor-based therapeutics. Taken together, our data highlight the potential of LCK-targeting MGDs as a strategy to overcome kinase inhibitor resistance in T-ALL, offering a framework for targeting kinase dependencies in drug-refractory hematologic malignancies more broadly.

The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. Although mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 coregulates divergent cell fates remains incompletely characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome (MDS) and myeloid leukemia of Down syndrome, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Therefore, we hypothesized that chromatin accessibility determines GATA1 cistrome specificity and lineage fate decisions. To understand the connection between chromatin accessibility and GATA1, we comprehensively studied erythropoiesis in Stag2Δ mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid differentiation, increased number of megakaryocyte progenitors, and increased megakaryocytes. RNA- and assay for transposase-accessible chromatin-sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Despite unchanged Gata1 expression, Gata1 occupancy was reprogrammed from erythroid to megakaryocyte targets with Fli1 motifs enriched at Stag2Δ Gata1 binding sites. Functionally, we observed that Stag2-deficient EryPs have a diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays, which was partially reversed with Fli1 knockdown. Human models and patients with primary MDS recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study establishes chromatin accessibility as a determinant of transcription factor binding specificity, revealing an accessibility-driven Gata1 retargeting mechanism underlying MDS dyserythropoiesis.

Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell malignancies, yet challenges including manufacturing delays, T-cell exhaustion, and limited persistence impede broader clinical success. Here, we report the single-day production of nonactivated CAR T cells engineered to secrete interleukin-18 (IL-18), a proinflammatory cytokine that enhances T-cell function. These nonactivated CART19-IL-18 cells (IL-18-secreting anti-CD19 CAR T cells) exhibit robust antitumor efficacy across xenograft models of lymphoma, leukemia, and pancreatic cancer. IL-18 expression enhances the functional advantages of naïve-like nonactivated CAR T cells, resulting in improved persistence, metabolic fitness, and resistance to exhaustion. Single-cell transcriptomic analysis revealed upregulation of IL7R, KLF2, and MCL1, alongside suppression of inhibitory checkpoint genes such as PDCD1, TOX, and HAVCR2. Metabolomic profiling demonstrated enhanced mitochondrial bioenergetics, with increased spare respiratory capacity and accumulation of α-ketoglutarate, malate, and spermine. Functional in vitro and in vivo profiling demonstrated enhanced per-cell cytotoxicity and in vivo durability. We complemented these studies with single-cell transcriptomic and metabolomic analyses to define CAR T-cell biological states beyond what is captured by xenograft tumor clearance. This IL-18-enhanced, activation-free CAR T-cell product offers a clinically actionable platform with the potential to reduce vein-to-vein time while improving product potency and persistence, providing a rationale for clinical testing in patients with tumors refractory to standard CAR T-cell therapy.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the neoplastic transformation of immature T cells during their development in the thymus. Deciphering the developmental programs whose dysregulation drives T-ALL pathogenesis is critical for the development of novel targeted therapies, which remain an urgent unmet need for the treatment of this disease. MicroRNAs (miRNAs) have emerged as key posttranscriptional regulators of numerous physiological processes, including cancer. However, the specific role of miRNAs in human T-cell development and T-ALL pathogenesis remains largely unexplored. In this study, we comprehensively evaluated miRNA expression profiles across human T-cell development using microarray analysis and identified a dynamic expression pattern of miR-16-2, which is upregulated during early pre-T-cell proliferative stages up to the resting stage of immature thymocytes immediately preceding T-cell receptor αβ expression and is subsequently downregulated. We also confirmed the coordinated regulation of miR-15b expression, consistent with the reported clustered genomic location of both miRNAs. Notably, functional studies identified the miR-15b/16-2 cluster as a negative regulator of early thymocyte proliferation and demonstrated that overexpression of miR-15b/16-2 in T-ALL cells impaired leukemic growth in vitro and tumor progression in patient-derived xenotransplantation assays. Mechanistically, miR-15b/16-2 represses the expression of the genes encoding BCL-2 and cyclin D3, thereby promoting apoptosis and cell cycle dysregulation in T-ALL cells, characterized by an accumulation of G0-phase cells and a defective transition to the G2/M phase. Overall, these findings support a novel tumor-suppressive function for miR-15b/16-2 in T-ALL and highlight its potential as a promising therapeutic target.

The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations, and nucleoporin 98 rearrangements and represents an emerging opportunity for therapeutic intervention. Here, we report the development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent, and selective small-molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential, and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9, and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction in the menin-KMT2A target genes. We next assessed ziftomenib against 4 MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor, revumenib. Ziftomenib retained antileukemic activity against T349M mutant cells and demonstrated low nanomolar potency (50% growth inhibition ≤ 25nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas the M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M, or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing the potent inhibitory activity toward these mutants. Ziftomenib has recently received US Food and Drug Administration approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively induces rapid liver hypertrophy in patients with initially unresectable liver tumours, yet the immunological mechanisms remain unclear. We aim to elucidate the immune alterations and underlying mechanisms driving liver regeneration following ALPPS. The cohort study included single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on remnant liver tissues from ALPPS patients. Neutrophil infiltration was validated by flow cytometry and histological analyses in the world's largest ALPPS clinical cohort and mouse ALPPS models. Functional validation, including neutrophil depletion, matrix metalloproteinase 9 (MMP9) inhibition and CD177 blockade, as well as Cd177 knockout and CD177+ neutrophil infusion in vivo. scRNA-seq revealed substantial neutrophil infiltration following stage 1 ALPPS. Depletion of neutrophils impaired liver regeneration. Among subsets, CD177+ neutrophils were metabolically active with enhanced neutrophil extracellular traps formation and secreted MMP9. MMP9 inhibition disrupted extracellular matrix (ECM) degradation and hepatocyte growth factor alpha (HGF-α) release, impairing regeneration. CD177+ neutrophils interacted with endothelial cells via CD177-PECAM1 to facilitate transmigration, while hepatic stellate cell-derived CXCL8 promoted neutrophil chemotaxis via CXCL8-CXCR1/2. Cd177 deficiency attenuated neutrophil infiltration and regenerative growth, while CD177+ neutrophil infusion restored regeneration, which was abolished in Cd177-/- mice. CD177+ neutrophils drive liver regeneration by promoting endothelial transmigration, ECM degradation and HGF-α release. These findings reveal a neutrophil-mediated mechanism driving surgical liver regeneration and support the potential of CD177+ neutrophil infusion to establish a proregenerative hepatic environment for therapeutic strategies in liver failure.

Selenoprotein F (SELENOF) is one of the 25 human selenoproteins that is highly sensitive to fluctuations in bioavailable selenium, an essential micronutrient. Although SELENOF has been implicated in cancer etiology, its precise role remains unclear. To define its contribution to carcinogenesis, Selenof knockout (KO) mice were exposed to the potent carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) and fed a high-fat, high-calorie Western diet. All Selenof KO mice developed tumors and did so more rapidly, whereas only 30% of wild-type mice developed tumors. This effect was further exacerbated by the Western diet regardless of Selenof status. Notably, the majority of DMBA-induced tumors in KO mice were skin lesions, predominantly cutaneous squamous cell carcinomas (SCCs) and benign papillomas. These tumors occurred at a four-fold higher frequency in KO mice than in wild-type controls, establishing SELENOF as a key tumor suppressor in the skin. To assess the relevance of these findings to human disease, we analyzed a skin cancer microarray containing patient samples of SCC, basal cell carcinoma, melanomas, and matched adjacent normal tissue. SELENOF expression was dramatically reduced across all tumor types relative to normal skin. Although the skin of Selenof KO mice appears histologically normal, transcriptomic profiling followed by enrichment analysis revealed significant downregulation of pathways related to epidermal development and keratinocyte differentiation as well as the upregulation of oxidative phosphorylation and mitochondrial metabolic pathways. Collectively, these findings support a causal link between SELENOF loss and skin cancer development and highlight a previously unrecognized role for SELENOF in safeguarding against skin carcinogenesis. Significance: Skin cancers are the most common human malignancies. SELENOF levels are significantly reduced in skin cancers, and experimental evidence establishes a critical tumor-suppressive role for SELENOF in the skin.

Spatiotemporal control over supramolecular assemblies holds promise for precise theranostics, yet conventional designs often require an extensive modification of the backbone by introducing responsive motifs. Herein, with minimal interference of the molecular backbone, we report a chiral engineering strategy to enhance the pH sensitivity of a tripeptide-drug conjugate (PDC). Specifically, homochiral PDC forms supramolecular nanofibers with a low pH dependence, whereas the heterochiral isomer with alternating D/L residues exhibits a highly pH-dependent self-assembly. Importantly, in carbonic anhydrase IX (CAIX)-overexpressing tumor cells, fibrous assemblies of homochiral PDCs occur at the cell surface, while heterochiral PDCs form nanofibers within lysosomes via protonation. This process subsequently promoted lysosomal membrane permeabilization and enhanced CAIX inhibition, which turns into an efficient way of enhancing cellular Fenton reactions to evoke ferroptosis, thereby improving the antitumor efficacy in breast tumors. Overall, this work proposes a chiral engineering approach for enhancing the pH sensitivity of supramolecular assemblies, which establishes an efficient strategy for spatiotemporal control over supramolecular assemblies and offers alternative insights into the biological effects of heterochirality.

A rational design for facilitating innovative cell death modes can substantially aid advances in antitumour therapy1,2. Here we design and implement a unique mode of immunogenic membranolytic cell death (mLCD) in tumour cells, characterized by time-lagged rupture from the lysosomal to plasma membranes; this approach was found to robustly potentiate immune checkpoint blockade therapy. This mode of mLCD was induced by the synthetic-acid-responsive membranolytic peptide (aMP) aMPC16-CA50, which exhibits hierarchical responsiveness to the decreasing pH associated with the tumour extracellular environment and lysosomes. aMPC16-CA50 activated an inflammatory transcriptional program in tumour cells, potentiating their ability to induce antigen presentation on class I major histocompatibility complex molecules on dendritic cells and the subsequent activation of T cells. The pH-responsive kinetics and membranolytic activity of the membranolytic peptides had a critical role in enhancing the immunogenicity of lytic tumour cells through the spatiotemporal regulation of the membrane-rupture processes. Furthermore, aMPC16-CA50 exhibited a considerable advantage in enhancing the antitumour efficacy of immune checkpoint blockade therapy through the promotion of antitumour immune response. Moreover, its systemic administration was well tolerated in mice. Overall, we successfully programmed a unique mode of immunogenic mLCD in tumour cells through the spatiotemporal regulation of membrane-rupture processes using a synthetic pH-responsive membranolytic peptide amenable to manipulation.

The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.

Despite advances in precision oncology, effective personalized treatments are still lacking for most patients with cancer1. The Cancer Dependency Map (DepMap) accelerates this field by systematically identifying cancer vulnerabilities in diverse preclinical models. Data from over 1,300 cell lines have led to the discovery of new therapeutic strategies across multiple tumour types2. However, mapping cancer vulnerabilities using traditional cell lines has limitations, including insufficient cancer subtype representation and the impact of culture conditions on perturbation responses. Here we perform 147 genome-scale CRISPR screens and multi-omic characterizations of next-generation (NextGen) cancer models (organoids and spheroids) across 10 cancer types. This strategy enables the expansion of DepMap to cover new genomic and molecular subtypes and to identify new biomarker-associated vulnerabilities. These new models also preserve transcriptional programs that are silenced in traditional cell lines and facilitate the discovery of specific gene dependencies associated with these programs. Comparisons of traditional and NextGen cancer models enable further identification of distinct effects of growth format and culture medium on gene essentiality. The integrated dataset combines data from both model types to offer a valuable, expansive resource for exploring cancer vulnerabilities and is accessible via the DepMap portal.

Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile-drug conjugates is analogous to that of antibody-drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.

Emerging evidence now points to innate tissue immunity as a critical orchestrator of both local tissue adaptation and long-range hematopoietic reprogramming, including the amplification of emergency granulopoiesis through bone marrow progenitor remodeling. These findings position the intestine as an instructive niche capable of imprinting long-lived changes both locally and systemically. This review synthesizes current findings at the intersection of gut and bone marrow biology, examining how intestinal inflammation shapes granulopoietic output and how bone marrow-derived effectors, in turn, reinforce maladaptive tissue responses that underlie chronic intestinal manifestations, including colitis-associated cancer and extraintestinal inflammatory complications frequently seen in IBD. We delineate the physiological framework governing these regulatory nodes and highlight the translational implications for next-generation therapeutic intervention.

Chronic stress is increasingly recognized as a driver of cancer metabolism, highlighting the need to elucidate the mechanism linking chronic stress to metabolic reprogramming. Here, we performed untargeted metabolomics on serum samples from esophageal squamous cell carcinoma (ESCC) patients and integrated the results with clinical and stress-related assessments, revealing pentose phosphate pathway (PPP) enrichment accompanied by elevated epinephrine levels in patients with stress-associated features. β2-adrenergic receptor (ADRB2) activated by chronic stress stabilized MYCBP by competitively displacing VHL, thereby enhancing MYC transcriptional activity and upregulating key PPP enzymes, including G6PD and TKT. Unexpectedly, stress-associated stimulation not only activated ADRB2 signaling but also increased ADRB2 protein abundance. Mechanistically, stress exposure enhanced RNMT-dependent N7-methylguanosine (m7G) cap modification of ADRB2 mRNA, thereby increasing its translational efficiency. Together, these findings define an RNMT-ADRB2-MYCBP-PPP axis that integrates epitranscriptomic regulation with adrenergic signaling to promote metabolic reprogramming and malignant progression in ESCC. The stress-associated RNA modification-metabolism circuitry comprises potential therapeutic targets to overcome stress-associated ESCC progression.

Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays critical regulatory roles in multiple signaling pathways by preventing the ubiquitin-mediated degradation of its substrates. Dysregulated expression of USP7 is implicated in tumor progression; however, its role in renal fibrosis remains unclear. In the present study, USP7 was observed to be significantly upregulated in the kidneys of patients with chronic kidney disease (CKD), which correlated with fibrotic lesions and renal dysfunction. Both genetic depletion and pharmacological blockade of USP7 significantly attenuated fibroblast activation and extracellular matrix deposition in two mouse models of kidney fibrosis-unilateral ureteral obstruction and unilateral renal ischemia-reperfusion injury models, indicating a pro-fibrotic function of USP7. Mechanistically, intergrated proteomic sequencing and phosphoproteomic sequencing revealed that USP7 modulated the tuberous sclerosis complex 1 (TSC1)-mTOR pathway. USP7 knockdown restored TSC1 expression and inhibited mTOR activation. However, USP7 did not directly interact with TSC1; instead, it deubiquitinated and stabilized lysine-specific demethylase 5B (KDM5B), which subsequently reduced histone H3K4me3 modification at the Tsc1 promoter to repress its transcription. Conversely, the inhibition of USP7 promoted KDM5B degradation, thereby restoring TSC1 expression and suppressing mTOR-driven fibrogenesis. Thus, these findings identify USP7 as a critical promoter of renal fibrosis, acting at least in part through the KDM5B-TSC1-mTOR axis. This highlights USP7 as a potential therapeutic target for CKD.

Metastasis remains a leading cause of mortality in esophageal squamous cell carcinoma (ESCC) patients, underscoring the urgent need to elucidate the molecular mechanisms driving disease progression. In this study, we delineated that ZBED2, a zinc finger protein, correlates with inferior survival outcomes and metastasis in ESCC patients. ZBED2 formed phase-separated nuclear condensates that functionally promote tumor metastasis, and integrin-linked kinase (ILK) was pinpointed as a critical downstream effector in mediating the pro-metastatic function of ZBED2. Mechanistically, ZBED2 enhanced the transcription of HSP90AA1, promoted the physical interaction between HSP90AA1 and ILK, and consequently stabilized ILK by suppressing its ubiquitination. Subsequently, ILK promoted PD-L1 transcription and CD8+ T cell exhaustion, thereby creating an immunosuppressive microenvironment that facilitates cancer metastasis. Collectively, these findings establish the pivotal role of ZBED2 in driving ESCC metastasis and immune evasion, thereby validating it as a promising therapeutic target for this aggressive malignancy.

Manganese-ion-based nanoparticles have emerged as highly versatile platforms that seamlessly integrate diagnostic and therapeutic functions, enabling precision cancer theranostics. In this review, we discuss manganese-based nanomaterials through a design-oriented framework that connects synthesis, structure, function, application, and limitation. Mainstream preparation strategies, including thermal decomposition, permanganate reduction, hydrothermal/solvothermal synthesis, template-assisted construction, coprecipitation, and mild biomimetic routes, are compared with respect to physicochemical control, Mn activation behavior, scalability, and biomedical suitability. The diagnostic applications of manganese-based nanoplatforms are discussed, including activatable T1-weighted magnetic resonance imaging (MRI) and multimodal imaging systems, as well as Mn-activated DNAzyme platforms for gene regulation. We further review therapeutic modalities enabled by Mn2 +, encompassing chemodynamic therapy (CDT), nanozyme-mediated redox regulation within the tumor microenvironment, stimulus-responsive drug and prodrug delivery, magnetic hyperthermia, and their synergistic combinations. Finally, we critically analyze key biosafety considerations along with current translational challenges and future perspectives for developing clinically viable, image-guided combination cancer therapies based on manganese-ion nanoplatforms.

Cancer and inflammatory diseases are critically influenced by dynamic interactions between pathological tissues and the host immune system. The precise migration of immune cells into the local microenvironments of tumors or inflammation is a fundamental prerequisite for them to exert their functions. Immune reservoirs, including tertiary lymphoid structures, secondary lymphoid structures, bone marrow and the intestinal tract, serve as critical mobilization hubs for diverse lymphoid and myeloid populations to infiltrate tumors or inflamed sites. The directional migration of immune cells is orchestrated through complex regulatory networks involving chemokine or cytokine-receptor pairs, adhesion molecule interactions, extracellular vesicle signaling, metabolic reprogramming and microbiota modulation. In both tumors and inflammation, immune cell trafficking shapes the local immune landscape, contributing to either immune protection or pathological progression. Contemporary therapeutic strategies targeting immune cell migration encompass the following axes: precision modulation of chemokine or cytokine networks, architectural reprogramming of lymphatic structures or extracellular matrix, dietary intervention and strategic manipulation of microbiome. Nevertheless, clinical translation remains hindered by microenvironmental heterogeneity, suboptimal migratory efficiency, and technical limitations in longitudinal tracking of cellular dynamics. This review integrates recent findings from oncology and inflammatory diseases to explore the origins, phenotypes and trafficking mechanisms of migratory immune cells, highlighting how advances in understanding immune migration across cancer and inflammation can inform therapeutic innovation and precision immunomodulation.

Conventional cyanine photosensitizers face challenges in photodynamic therapy (PDT) due to poor intersystem crossing (ISC), hypoxia sensitivity, and low tumor retention. Herein, we report the first asymmetric D-π-A-D' cyanine dyes with hybridized local and charge-transfer (HLCT) characteristics to address these limitations. By precisely regulating triplet excitons of the T2 state, these dyes facilitate enhanced ISC from the S1 to T2 state and boost reactive oxygen species (ROS) generation. These HLCT-type cyanine dyes integrate the charge-transfer state to promote oxygen-independent Type I PDT for hypoxic tumor environments and the locally excited state to maintain high photoluminescence quantum yield (PLQY) for visualized tumor therapy. Among them, CyTY-3 exhibits exceptional dual Type I/II PDT performance, with a singlet oxygen yield outperforming ICG by 27.8-fold, while simultaneously delivering a high NIR-II PLQY of 11.4% for high-contrast imaging. Unique delocalized charge distribution enables excellent tumor targeting and an ultralong retention time of up to 12 days. In vivo, CyTY-3 nanoparticles achieve 99.01% tumor inhibition under 808 nm irradiation with good biosafety. This HLCT strategy provides a robust platform for developing next-generation photosensitizers to overcome the intrinsic limitations of hypoxic tumor therapy.

Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for targeted protein degradation but are frequently constrained by synthetic complexity and overreliance on a single-E3 ligase, leading to diminished efficacy in tumors with low or heterogeneous ligase expression. Here, we report a genetically encoded artificial self-splicing RNA (asRNA) platform that autonomously generates twin PROTAC effectors from a single transcript, enabling the coordinated recruitment of two distinct E3 ligases. Following transcription, the asRNA undergoes precise ribozyme-mediated self-cleavage to produce a peptide-based PROTAC that recruits the VHL ligase and an RNA aptamer-based PROTAC that engages the Dzip3 ligase, thereby activating complementary ubiquitination pathways. This dual-ligase architecture markedly enhances degradation of otherwise refractory oncogenic targets, including c-MYC and EGFR, resulting in pronounced antitumor efficacy in cancer models. The modular and programmable genetic design enables rapid reconfiguration of target-recognition elements without complex chemical synthesis. As the first single-transcript system to achieve coordinated dual-E3 ligase recruitment, this work establishes a new genetically encoded strategy for multivalent protein degradation and expands the scope of targets accessible to PROTAC-based strategies.

Induced covalent bond formation, or cross-linking, is a powerful strategy for interrogating and modulating biological systems. Current strategies rely largely on photochemical processes, which generally restrict their use to cellular or other optically accessible settings. Broadening the chemistry underlying the cross-linking-initiating event could extend these approaches to more complex biological systems. Ionizing radiation─a cornerstone of cancer therapy─is an attractive but unexplored trigger for covalent chemistry. Here, we detail the systematic comparison of a series of rationally designed radiolytic cross-linking candidates. These studies reveal that 2-alkyl furans efficiently label a representative protein in a radiation dose-dependent manner. Mechanistic analyses suggest that radiolysis induces hydroxyl radical-mediated oxidation of the furan, generating an electrophilic dicarbonyl intermediate that reacts with lysine residues to form stable adducts. We apply this strategy to enforce the covalent capture of an otherwise reversible small-molecule-protein interaction in cells. Together, these findings establish ionizing radiation as an effective trigger for covalent chemistry, expanding the scope of radiolytic chemistry to include bond formation. This work provides a foundation for future applications leveraging spatially targeted radiation for target identification or the development of next-generation therapeutic strategies.

Prostate cancer (PCa) remains one of the most prevalent and lethal cancers in men, particularly in its metastatic form. Despite therapeutic advancements, resistance to therapy often leads to a castration-resistant state with genetic and molecular alterations that promote immune evasion and disease progression. Chronic inflammation and the immunosuppressive tumor microenvironment (TME) further exacerbate immune dysfunction. The suboptimal clinical success of current immunotherapies in advanced PCa underscores the urgent need to better understand the mechanisms underlying immune escape during disease progression and in response to therapeutic interventions. This review explores the key immune-evasive features of PCa, the contribution of the TME, and the immunotherapeutic strategies that have been clinically evaluated to improve outcomes in patients with advanced disease.

Orally administered small-molecule programmed death ligand 1 (PD-L1) inhibitors may have the potential to improve patient outcomes in the treatment of a range of cancers compared with their antibody-based counterparts. A small molecule might achieve better tumor tissue penetration, and oral administration could significantly improve convenience and access for patients. Three phase 1 open-label, non-randomized, dose escalation, and expansion studies evaluated the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of three agents in patients with advanced solid tumors: INCB086550 (NCT03762447), INCB099280 (NCT04242199), and INCB099318 (NCT04272034). Overall, 138, 182, and 104 patients received INCB086550, INCB099280, and INCB099318, respectively. Most had previously received ≥2 lines of cancer therapy for advanced or metastatic disease; 9.6%-16.5% had received prior immunotherapy. All three agents were rapidly absorbed and showed stable dose-dependent PK. With INCB086550, 88 patients (63.8%) had ≥1 treatment-related treatment-emergent adverse event (TEAE), and 19 (13.8%) had ≥1 treatment-related grade ≥3 TEAE. In total, 14 patients (10.1%) had a nervous system-associated TEAE for which an immune-mediated etiology could not be ruled out; events were predominantly peripheral sensory and motor neuropathies. With INCB099280 and INCB099318, 144 (79.1%) and 69 (66.3%) of patients had ≥1 treatment-related TEAE, and 25 (13.7%) and 12 (11.5%) had ≥1 treatment-related grade ≥3 TEAE, respectively. The most frequent immune-related adverse events were skin reactions (INCB099280 and INCB099318) and hepatitis (INCB099280). No dose-limiting toxicities (DLTs) occurred during dose escalation with INCB086550 or INCB099318; two DLTs occurred in two patients with INCB099280 (grade 2 vomiting with 600 mg once daily and grade 2 maculopapular rash with 800 mg two times per day). Overall objective response rates for INCB086550, INCB099280, and INCB099318 were 10.9% (95% CI 6.2% to 17.3%; n=15), 8.8% (95% CI 5.1% to 13.9%; n=16), and 8.7% (95% CI 4.0% to 15.8%; n=9), respectively. Target engagement and PD activity were demonstrated, including PD-L1 binding, and increases in cytokine and chemokine production, as well as T-cell activation and proliferation. Both INCB099280 and INCB099318 had an acceptable safety profile, with preliminary evidence of antitumor activity. The risk of immune-mediated neuropathy led to discontinuation of the clinical program for INCB086550.

Psoriasis progresses to psoriatic arthritis in up to 30% of patients, causing irreversible joint damage and substantial healthcare burden. Whether biologic therapy reduces psoriatic arthritis risk remains unclear. The aim of this paper was to evaluate the association between biologic therapy and psoriatic arthritis risk in psoriasis patients. We conducted a systematic review and meta-analysis of cohort studies (PROSPERO: CRD420251240466), searching PubMed, EMBASE, and Cochrane Library from inception to December 2025. We included cohort studies of adults with psoriasis without prior psoriatic arthritis that reported adjusted risk estimates for incident psoriatic arthritis and used an 'on-drug' analytical framework to account for changes in treatment status over time. Pooled hazard ratio (HRs) with 95% confidence interval (CI) were calculated using fixed- or random-effects models. In total, 15 cohort studies including 124,138 psoriasis patients with over 778,690 person-years of follow-up were included. Biologic use was associated with a 46% lower psoriatic arthritis risk versus non-biologic therapy (pooled HR 0.54, 95% CI 0.43-0.68), consistent versus non-systemic therapies (HR 0.57, 95% CI 0.33-0.97) and methotrexate (HR 0.48, 95% CI 0.45-0.51). Interleukin (IL)-17 inhibitors (HR 0.65, 95% CI 0.49-0.87; 3 studies) and IL-12/23 or IL-23 inhibitors (HR 0.46, 95% CI 0.36-0.60; 4 studies) were associated with lower psoriatic arthritis risk than tumor necrosis factor inhibitors. IL-23 inhibitors showed greater protection than IL-17 inhibitors (HR 0.67, 95% CI 0.58-0.77), while IL-23 inhibitors and IL-12/23 inhibitors did not differ (HR 0.88, 95% CI 0.69-1.13). Biologic therapy for psoriasis, particularly IL-23/IL-17-targeted agents, is associated with reduced incident psoriatic arthritis risk. These findings suggest early pathway suppression may delay clinical psoriatic arthritis diagnosis, though causal inference is limited by the observational data.

Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compensated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased soluble MAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.

The prevailing notion is that effector T cell activation mediates anti-PD-1 efficacy in cancer. Here, we conducted a mechanistic study parallel to our phase 2 trial of perioperative anti-PD-1 therapy in patients with resectable recurrent hepatocellular carcinoma (HCC) (NCT04615143) to study its mechanism of action. Late-recurrence patients present two distinct subtypes characterized by T cell or B cell dominant responses in the tumor microenvironment by dynamic single-cell multi-omics analysis. Clonal antibody repertoire analysis and spatially paired scRNA-seq/BCR-seq reveal somatic hypermutation promoting antibody binding against hepatitis B virus core antigen (HBcAg) within tumor tertiary lymphoid structures (TLSs) in these type B-late recurrence patients. Mechanistically, HBcAg is exported into the extracellular space, triggering local B cell and antibody responses and complement activation. In mice, these high-affinity HBcAg-reactive antibodies lead to complement-mediated antitumor activity with enhanced anti-PD-1 efficacy. Thus, we uncover enhanced anti-virus B cell immunity within the TLS as a mechanism to anti-PD-1 in HCC.

Lung cancer remains a leading cause of cancer-related mortality worldwide, and the clinical translation of chimeric antigen receptor (CAR)-based immunotherapy into solid tumors continues to be constrained by antigen heterogeneity, an immunosuppressive microenvironment, and stromal barriers that impede immune cell trafficking and curtail efficacy. Here, we present a comprehensive bibliometric analysis of CAR-based immunotherapy for lung cancer, drawing on publications indexed in the Web of Science Core Collection and Scopus between 2016 and 2025. Bibliometric and network analyses elucidate global research trajectories, collaboration patterns, and emergent therapeutic themes, while clinical trial data from ClinicalTrials.gov further appraise translational progress. This landscape has expanded rapidly, with growing emphasis on CAR engineering, microenvironment modulation, precision targeting, and combinatorial strategies. Clinical evidence, though drawn from a still-limited number of trials, indicates generally tolerable toxicity in most reported cases; nevertheless, severe and occasionally fatal adverse events have been documented, underscoring the need for continued vigilance in safety evaluation. Antitumor efficacy remains modest, reflecting persistent challenges in target selection, tumor accessibility, cellular persistence, and functional maintenance. Emerging strategies, including multi-target CAR architectures, rational drug combinations, and biomarker-guided patient stratification, may offer avenues for overcoming these limitations. This study furnishes a data-driven pharmacological atlas of CAR-based immunotherapy in lung cancer, illuminating key therapeutic targets, evolving treatment paradigms, and prospective opportunities for clinical translation.

Survival in metastatic pancreatic ductal adenocarcinoma (mPDAC) has long been limited by a dismal second-line therapeutic ceiling dictated by conventional chemotherapy. However, breakthrough data from the ASCO 2026 Annual Meeting and the publication of the phase III RASolute-302 trial mark a definitive shift toward targeted KRAS inhibition. This correspondence highlights how the first-in-class pan-RAS (ON) inhibitor daraxonrasib (RMC-6236) virtually doubled median overall survival (13.2 vs. 6.6 months) and progression-free survival compared to chemotherapy in second-line mPDAC, establishing a new standard of care. Concurrently, we evaluate emerging allele-specific strategies from ASCO 2026 designed to optimize target engagement and safety. These include the selective KRAS G12D inhibitor DN022150 and promising horizontal combinations pairing the G12D inhibitor HRS-4642 with either the anti-PD-L1 antibody adebrelimab or a Nectin-4-targeted antibody-drug conjugate (ADC). Furthermore, we address the KRAS G12C cohort where farnesyl transferase co-inhibition (darlifarnib plus adagrasib) successfully bypasses adaptive resistance. Ultimately, the therapeutic landscape of mPDAC is transitioning toward tailored genomic frameworks. Future success will rely on optimizing the clinical sequencing or combination of pan-RAS and allele-specific agents, guided by real-time liquid biopsies, to permanently dismantle resistance and transform mPDAC into a manageable molecular entity.

Natural killer (NK) cell-based immunotherapy is an increasingly important cancer treatment strategy because of its innate cytotoxicity, allogeneic potential, and compatibility with off-the-shelf manufacturing. We analyzed 287 clinical trials identified in the INFORMA database to characterize the global development of NK-cell therapies across phases, regions, indications, combinations, cell sources, product origins, and engineering platforms. Most trials were planned or early-phase, and combination regimens were more frequent than monotherapy. The USA, China, and South Korea led clinical activity. Hematologic malignancies remained the principal testing ground, while lung, colorectal, and other solid tumors reflected broader expansion. Platform-level analysis showed a predominance of allogeneic products and rapid growth of CAR-engineered NK-cell trials after 2020. These findings indicate a transition from proof-of-concept adoptive transfer toward standardized, genetically programmable, off-the-shelf platforms. The principal challenge is shifting from manufacturing feasibility alone to durable biological activity. Future development should align cell engineering, combination partners, translational endpoints, and biomarker-guided patient selection with specific barriers involving persistence, tumor delivery, microenvironmental fitness, and immune escape.

Nearly half of patients with melanoma do not respond to immune checkpoint inhibitors (CPIs) and many develop immune-related adverse events (irAEs), often forcing treatment discontinuation, and underscoring the need to predict and monitor outcomes. Responses may depend on both B cell and T cell activity. We performed high-dimensional mass cytometry profiling of coexisting peripheral B cell and key T cell states in treatment-naïve patients and healthy individuals, and paired longitudinal samples from CPI-treated patients, with clinical annotations to define immune correlates of outcomes. CPI-naive patients exhibited reduced CD19+ B cells, reduced B cell (CD21, IL-2, CXCR5) and T cell (CD38, CD27) activation markers, alongside enriched naïve (CD21lo) and double-negative (DN2)-like B cells, CD95+IL-10+plasmablasts, consistent with extrafollicular responses. Concurrently, programmed cell death protein 1 (PD-1)+ and proliferation marker protein-67 (Ki67)+ T cell expansion indicates ongoing activation with features of proliferative exhaustion. Active disease featured increased regulatory CD95 expression on B cells and expanded T follicular helper-like and activated DN (CD4-CD8-) T cells, indicating sustained antigen stimulation. Pretreatment, elevated PD-1+ T cells predicted irAEs, whereas VEGF (vascular endothelial growth factor)+TGF-β (transforming growth factor-β)+ DN T cells were enriched in patients without subsequent toxicity. Pretreatment, plasmablasts, transitional B cells, Forkhead box protein P3 (FoxP3)+ and central memory-like CD8+ T cells correlated with worse overall survival; naïve CD21lo B cells, PD-1+CD8+ T cells and CD4+follicular helper-like T cells predicted shorter event-free survival; CD4+ memory T cells predicted better prognosis, implicating dysregulated differentiation and sustained activation in adverse outcomes. On-treatment, naïve CD21hi B cells, plasmablasts, activated CD8+ and central memory-like CD4+ T cells expanded, indicating de novo humoral responses and cytotoxic T cell invigoration. On-treatment, increased class-switched memory (IgG2+) B and activated T cells predicted improved survival, while persistent naïve and DN B cells were associated with poorer outcomes. Anti-PD-1 monotherapy expanded naïve (CD21hi) B cells and global T cells. Anti-PD-1/anti-LAG-3 (lymphocyte-activation gene 3) combination contracted memory B cells. Melanoma displays aberrant peripheral B and T cell activation, maturation and exhaustion, prominent in active disease. Treatment-induced class-switched B cells and T cell invigoration predict clinical benefit and naïve/DN B cells signify resistance. Coordinated B and T cell responses, especially recurrent extrafollicular B cell and exhausted/regulatory T cell states emerge as candidate indicators of outcome.

Recurrent glioblastoma (rGBM) is a leading brain malignancy with few therapeutic options. Here we present the complete results of a phase 1 trial investigating the safety and efficacy of autologous B7-H3-targeting chimeric antigen receptor T (CAR-T) cell (TX103) therapy for the treatment of rGBM. In this open-label, 3 + 3 dose-escalation trial, patients aged 18-75 years with B7-H3-positive (≥30%) rGBM received intracranial infusion of TX103 at three dose levels (DLs-2 × 107, 6 × 107 and 1.5 × 108 cells per infusion). Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included survival, pharmacokinetics and immunological response. Fifteen patients received a total of 72 intracranial infusions and 13 underwent repeated infusions. TX103 therapy was well tolerated, with no dose-limiting toxicities or MTD identified. Treatment-related adverse events (TRAEs) included low-grade cytokine release syndrome (86.7%), sinus tachycardia (53.3%), vomiting (53.3%), hypertension (53.3%) and elevated intracranial pressure (46.7%). Three grade 3 TRAEs considered serious adverse events occurred (elevated intracranial pressure, epilepsy and depressed consciousness), two at DL3. The 12-month overall survival (OS) rate was 66.7% and median OS was 19.1 months (95% confidence interval = 8.93, not reached) from first infusion. Disease control (stable disease or better) was achieved in 8 of 14 patients with measurable disease, including one complete response sustained through the latest follow-up. Cerebrospinal fluid showed a marked increase in CAR gene copy numbers and cytokine release, with minimal peripheral activity and no cumulative toxicity after repeated infusions. In conclusion, intracranial TX103 infusion demonstrated acceptable safety and encouraging efficacy in rGBM, supporting a future phase 2 evaluation at the RP2D (DL2, 6 × 107 cells per infusion). ClinicalTrials.gov registration: NCT05241392 .

First-line immune checkpoint inhibitor (ICI) therapy has contributed to improved outcomes in hepatocellular carcinoma (HCC). However, only around 30% of patients respond, highlighting the need for biomarker-driven patient selection. Considering the lack of tissue acquirement in HCC in clinical routine, liquid biopsy holds great promise. We aimed at profiling immune checkpoints (IC) on circulating extracellular vesicles (EVs) as potential liquid biopsy-based biomarkers for prediction of treatment response. Three distinct cohorts were analysed in this study: (1) HCC explorer cohort (n=40), testing the presence of membrane-bound ICs on EVs; (2) early-stage HCC cohort (n=37 with paired blood and tissue), assessing the interplay between EV and tissue ICs alongside clinicopathological parameters and (3) treatment cohort (n=202 with 600 sequential blood samples), comprising an ICI treated cohort with a training (n=79, n=402 sequential samples) and a validation group (n=82, n=146 sequential samples), alongside a tyrosine-kinase inhibitor (TKI) treated cohort (n=41, n=52 sequential samples), to identify predictors of immunotherapy response through IC profiling of circulating EVs via multiplex immunoassay. Programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) were enriched in EV fractions compared to EV-depleted serum. Baseline and early dynamics of EV-IC levels significantly discriminated between responders and non-responders in the ICI-treated training and validation cohorts, while simultaneously predicting progression-free survival (PFS) and overall survival (OS). These findings were not reproducible in the TKI-treated cohort. In addition, dynamic changes of EV-IC levels during therapy in patients with initial response predicted acquired therapeutic resistance, approximately 36-42 weeks before progression was traceable on imaging. EVs carrying PD-1, PD-L1 and CTLA-4 represent readily quantifiable, non-invasive biomarkers to predict response and survival in patients with advanced HCC undergoing ICI therapy and serve to identify biological ICI resistance much earlier than current standards with imaging.

Antigen-specific T-cell immunotherapies are transforming the treatment landscape of hematologic malignancies. Neoantigen-specific therapies that exploit the ability of endogenous T-cell receptors (TCRs) to recognize tumor-derived peptides in an HLA-restricted context differ mechanistically from modalities employing chimeric antigen receptor T cells, which target surface antigens in an HLA-independent manner. In contrast to approaches targeting tumor-associated antigens, neoantigen-specific strategies offer more precise tumor selectivity and reduced off-target toxicity. Advances in immunogenomics, immunopeptidomics, and functional validation have accelerated the identification of both personalized and recurrent neoantigens, and high-resolution sequencing technologies have further facilitated the characterization of their cognate TCRs, which are currently being explored for developing TCR-engineered T-cell therapies. Early-phase clinical trials in hematologic malignancies demonstrate that neoantigen-specific strategies are safe and feasible across multiple hematologic cancers, with ongoing studies actively assessing the immunogenicity, clinical efficacy, and durability of these approaches. This review synthesizes recent preclinical and clinical advances in the discovery, validation, and therapeutic exploitation of neoantigen-specific strategies in blood cancers, highlighting translational insights for prioritizing immunogenic neoantigens. Emphasis is placed on identifying biological and technological barriers that limit the therapeutic efficacy of neoantigen-specific immunotherapies, with the goal of distilling actionable insights to guide their development in hematologic malignancies.

Metastatic colorectal cancer (mCRC) is one of the deadliest cancers with very poor response to immune checkpoint blockade (ICB). Standard therapies employ chemotherapy combined with epidermal growth factor receptor (EGFR) blocking antibodies, which are only effective in a fraction of patients with RAS/RAF wild-type tumours. We have previously shown that EGFR deletion in myeloid cells of CRC, rather than in the cancer cells themselves, reduces tumour growth. Here, we investigate to which extent EGFR blockade in myeloid cells increases anti-tumour immunity, thus sensitising CRC to ICB. Using a syngeneic preclinical CRC liver metastasis model based on the transplantation of murine RAS mutant CRC organoids into mice lacking EGFR in myeloid cells, we observe a reduction in metastasis development accompanied by increased intratumoural T-cell infiltration. Importantly, we demonstrate that EGFR deletion reduces the capacity of granulocytic myeloid-derived suppressor cells (G-MDSCs) to suppress CD4+ T-cell proliferation. RNA-seq analysis of sorted MDSCs and T-cells uncovered an EGFR-dependent signature involved in immunosuppression, which in proficient-mismatch-repair (pMMR) CRC patients is associated with worse overall survival. Therapeutically, lifting immunosuppression by EGFR deletion in myeloid cells sensitised tumours to anti-PD-L1 treatment, thus preventing liver metastasis development. These results imply that anti-EGFR therapies combined with ICB might be successful in preventing metastasis of RAS mutated CRC with high infiltration of suppressive EGFR+ myeloid cells.

Gastrointestinal (GI) adenocarcinomas pose a significant therapeutic challenge due to highly immunosuppressive tumor microenvironments that limit effective antitumor immune responses. Dense stromal fibrosis, immune exclusion and poor responses to immune checkpoint inhibitors are hallmarks of treatment-resistant malignancies, most notably pancreatic ductal adenocarcinoma (PDAC) and subsets of gastric cancer. In this regard, IL-15 superagonists such as N-803, NIZ985, RLI, and NKTR-255 have emerged as promising immunotherapeutic candidates, as they selectively expand natural killer (NK) cells and CD8+ T-cells without the systemic toxicity and regulatory T-cell activation observed with IL-2 therapy. IL-15 superagonists have emerged as more effective therapeutic agents when used in conjunction with local inhibitors of TGF-β and IL-10, stromal remodelling, and vascular normalization. They are supported by increasingly conclusive mechanistic, preclinical and early clinical data. A combination of these interventions circumvents extracellular matrix-provoked immune barriers, reverses VEGF-induced endothelial dysfunction, and enhances the trafficking of lymphocytes into tumor cores. Moreover, several localized therapeutic delivery strategies, such as endoscopic delivery, implantable depots, biomaterial scaffolds, and nanocarriers, can improve intratumoral cytokine retention and reduce systemic inflammatory toxicity. Together, these advances define a new paradigm for cytokine-immunotherapy, with IL-15 superagonists serving as key mediators of reprogramming of the tumor microenvironment. Therapeutic strategies targeting IL-15 have the potential to restore cytotoxic immunity, improve access to immune cells, and promote responsiveness to the checkpoint blockade, making them a promising yet investigational approach to converting immune-cold GI malignancies into more treatment-responsive disease states, though further clinical validation is required.

Radiotherapy is frequently combined with chemotherapy, targeted therapy and immunotherapy to improve the efficacy of cancer treatment. Nevertheless, some radioresistant cancer cells seem to possess higher drug resistance, leading to failure of cancer treatment. Thus, it is crucial to explore the mechanisms of drug resistance in cancer RT. This review outlines molecular, cellular, and microenvironmental adaptations in cancer RT. These adaptations confer enhanced chemotherapy resistance in cancer cells surviving from ionizing radiation (IR). In addition, RT also activates oncogene signaling pathways, induces epigenetic remodeling and alters post-translational modifications, collectively driving resistance to targeted therapy. RT alters tumor intrinsic properties, promotes immunosuppressive effects and remodels TME, thus inducing immunotherapy resistance. Various emerging strategies including phytochemicals, small molecules, synthetic compounds, macromolecules, nanoparticles, photodynamic therapy (PDT), photothermal therapy (PTT), MicroRNA (miRNA) therapy, PROTACs, adoptive cell therapies, and engineered Salmonella, have been developed to overcome radioresistance and drug resistance in cancer RT. We highlight the importance of evaluating therapeutic effects and side effects of these emerging strategies. Through summarizing mechanisms and emerging strategies for drug resistance in cancer RT, this review aims to clarify obstacles in combined cancer treatment and guide future direction of research on cancer therapy.

Fasting-mimicking diets (FMD) have been reported to increase the anti-tumor efficacy in preclinical studies in various cancers. FMD can impact the tumor microenvironment (TME), and elucidating the mechanisms and cells mediating the effects of FMD may uncover combination treatment strategies. Here, we performed single-cell transcriptomic sequencing to characterize the TME changes induced by FMD intervention in a mouse model of spontaneous breast cancer. The sequencing data indicated that FMD suppressed tumor cell stemness, promoted apoptosis, and increased the infiltration of innate and adaptive immune cells, especially natural killer (NK) cells and effector CD8+T cells. Importantly, FMD induced phenotypic reprogramming of cancer-associated fibroblasts (CAFs), leading to a decrease in the immunosuppressive inflammatory CAF (iCAF) subset. Mechanistically, FMD decreased platelet-derived growth factor C (PDGFC) secretion in tumor cells by reducing glucose and inhibiting glycolysis to reprogram CAFs. PDGFC increased activation of the JAK/STAT3 pathway, which induced iCAF differentiation. Combining FMD with PDGFR inhibitors increased the efficacy of anti-PD-L1 immunotherapy in vivo. Overall, this study reveals a mechanism of metabolic-immune rewiring through which FMD suppresses tumor progression, providing preliminary evidence for the potential of combination FMD-based strategies in breast cancer treatment.

The clinical efficacy of cancer immunotherapy is fundamentally constrained by the synergistic evasion mechanisms of antigen concealment and effector immune cell suppression. To overcome these barriers, we proposed a therapeutic paradigm that sequentially dismantles the tumor's "immune camouflage" and relieves "metabolic coercion," thereby enabling systematic remodeling of the tumor immune microenvironment. A cascade-acting nano-Proteolysis Targeting Chimera (PROTAC) engine was fabricated via phosphatidylcholine-driven self-assembly, enabling tumor-targeted delivery and pH-responsive drug release within the tumor microenvironment. The system initially disrupted the tumor's immune evasion barrier by inducing cellular senescence and enhancing MHC-I-mediated antigen presentation. It subsequently reprogrammed tumor metabolism through targeted degradation of the BRD4/c-Myc axis, which alleviated nutrient competition and reversed the metabolic suppression of tumor-infiltrating T cells. This sequential intervention potently enhanced dendritic cell activation and antigen-presenting capacity, promoted the infiltration and reactivation of cytotoxic T lymphocytes, and synergistically induced PD-L1 degradation. Collectively, these coordinated effects established a durable antitumor immune response that potently suppressed both primary tumor growth and distant metastasis in a triple-negative breast cancer model. Overall, this work established a cascaded immune remodeling paradigm, conceptualized as unmasking and unblocking, offering a broadly applicable therapeutic strategy to overcome immunosuppression in solid tumors.

Innovations in therapeutic modalities and targeted drug delivery are two key approaches to improving the effectiveness of cancer treatment. With the development of therapeutic concepts and nanotechnology, recent research has shifted from tissue- or cell-level drug delivery to organelle-specific delivery to amplify therapeutic effects. Among these organelles, the endoplasmic reticulum (ER) has emerged as a particularly promising target because of its extensive membrane network, which serves as a major site for protein synthesis, lipid metabolism, calcium homeostasis, and intracellular signaling. The disruption of ER function can trigger severe cellular stress and apoptosis, providing a rationale for ER-targeted cancer therapy. However, traditional small-molecule drugs often exhibit poor ER specificity, rapid degradation, and limited intracellular accumulation, significantly restricting their therapeutic potential. In contrast, ER-targeting multifunctional nanoplatforms have demonstrated superior advantages, including enhanced stability, precise localization, controlled drug release, and multimodal therapeutic capabilities. In this Review, we systematically summarize the recent advances in ER-targeting nanotherapeutics and their applications in chemotherapy, phototherapy, immunotherapy, biotherapy, and combination therapy. Furthermore, we discuss the advantages, challenges, and mechanistic insights of these strategies, aiming to provide perspectives on accelerating the clinical translation of ER-targeting precision drugs.

Three-dimensional (3D) cell models, such as spheroids and organoids, are powerful tools to enhance the predictive power of preclinical in vitro studies and support clinical translation of anti-cancer therapies. However, their integration into drug discovery pipelines remains limited, particularly for high-throughput screening, where rapid and reliable viability assessment is essential. Conventional viability assays, often dye-based or destructive, remain labor-intensive and poorly suited for high-throughput applications and downstream re-use of the models. In this study, we demonstrate, for the first time, that electrical impedance spectroscopy (EIS) enables label-free viability profiling of individual spheroids. For this purpose, a differential EIS sensor was integrated into a plastic microfluidic chip in flow-through configuration with self-aligned facing electrodes. Using six probing frequencies, we measured the EIS responses of liver cancer spheroids exposed to varying concentrations of dimethyl sulfoxide and doxorubicin, a chemotherapeutic compound. We identified an optimized frequency pair that enabled us to monitor spheroid viability, independent of spheroid size. Comparison with conventional viability assays, namely fluorescence imaging and ATP quantification, confirmed that the EIS method reliably reflected viability changes and revealed inter- and intra-treatment group differences owing to the method's single-spheroid resolution. The same frequency pair could be used to detect viability changes for both compounds, suggesting transferability of the EIS method across treatments. Furthermore, we showed that utilizing additional EIS features improved classification of spheroids with subtle viability differences. Together, these results demonstrate that EIS is a promising approach for noninvasive, single-spheroid viability profiling and a valuable tool for high-throughput drug screening with spheroid models.

Prostate cancer (PCa) frequently metastasizes to bone, marking incurable disease. This progression is driven by an immunologically cold bone tumor microenvironment that fosters resistance to therapy. To define the mechanisms underlying this uniquely immunosuppressive niche, we applied spatial single cell analyses across primary tumors and metastatic sites. Bone metastases showed marked suppression of tumor-intrinsic type I interferon (IFN-I) signaling and loss of antigen presentation, features that were strongly associated with reduced bone metastasis-free survival. Tumor-intrinsic IFN-I expression correlated with memory T cell infiltration, whereas the bone myeloid compartment was enriched for protumor macrophages and showed reduced dendritic cell (DC) activation and antigen presentation. Digital spatial profiling of matched tumors revealed a broad loss of IFN-I-regulated immunostimulatory and checkpoint molecules. Notably, B7-H3, a putative negative regulator of IFN-I, was highly expressed in bone metastases and inversely associated with antigen presentation. These findings define bone-specific mechanisms of immune resistance and highlight therapeutic vulnerabilities that could inform precision therapeutic strategies for PCa.

High levels of immune suppression are a common intrinsic mechanism of resistance in metastatic breast cancer that calls for developing immunotherapeutic combinations to broaden treatment responses. Histone deacetylase (HDAC) inhibitors can sensitize tumors to dual checkpoint inhibition in patients. Here, we investigated the tumor microenvironment (TME) of breast metastases by combining experimental and clinical data with theory to elucidate the mechanism of response to treatment with the HDAC inhibitor entinostat combined with anti-PD-1 and anti-CTLA-4. Knowledge-guided subclustering of single-cell RNA-sequencing (scRNA-seq) data and cell circuit analyses from murine breast-to-lung metastases identified 39 cell states and salient interactions, of which myeloid, T cell, and B cell subpopulations were most affected. Analyses of patient biopsies and blood via spatial proteomics and flow cytometry corroborated the preclinical findings, showing increased T cell and B cell activation, mature tertiary lymphoid structures, and increased CD8+ T cell-macrophage distances in responders to entinostat + nivolumab + ipilimumab. Combination treatment increased immunoglobulin production in patients and mice, and murine studies demonstrated increased tumor-targeting IgG and implicated B cells as necessary for treatment response. Inhibition of the ICAM1 and IFNγ pathways in myeloid cells partially recapitulated treatment effects on CD8+ T cells observed via scRNA-seq. Mathematical modeling of tumor-immune dynamics implicated simultaneous modulation of multiple TME interactions as required for response to the combination treatment. Overall, this study identifies lymphoid and myeloid cell contributions to response to treatment with HDAC inhibitors and immune checkpoint blockade, providing a framework for discovering interactions driving responses in complex TMEs.

The high incidence and mortality rates of tumors have resulted in significant social and economic burdens, posing a major global threat to human life and societal development. In recent years, molecular targeted therapy for tumors has become a research hotspot. C-MET, the receptor for hepatocyte growth factor (HGF), plays a crucial role in the HGF/C-MET signaling pathway, which is involved in various processes such as tumor cell growth, invasion, migration, angiogenesis, epithelial-mesenchymal transition, tumor microenvironment remodeling and therapeutic resistance. Several C-MET-targeting strategies have been developed, including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs) against C-MET or HGF, antibody-drug conjugates (ADCs), nucleic acid aptamers, soluble receptors, natural compounds, and proteolysis targeting chimeras (PROTACs) targeting MET. These inhibitors have demonstrated encouraging anti-tumor effects in both preclinical and clinical studies, with several already available on the market. However, further research is still needed on the activation mechanisms of the HGF/C-MET signaling pathway and its interactions with other receptor tyrosine kinases, which will aid in identifying suitable patients for these treatments. This review provides a comprehensive overview of the structure, regulation, signaling pathways, and functions of C-MET, along with recent advances in C-MET inhibitors, offering valuable insights for cancer therapy.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized oncology, and its foundational logic-precise antigen recognition coupled with durable effector activity-extends naturally to chronic non-malignant diseases sustained by long-lived pathological cells. These include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue niches and evade clearance by conventional therapies. This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments. Co-stimulatory domains such as CD28, 4-1BB, and OX40 enhance persistence and effector function; programmed cell death protein 1 (PD-1)-CD28 switch receptors reverse inhibitory signaling; and cytokine-resistant CARs incorporating dominant-negative transforming growth factor-β (TGF-β) receptors maintain activity within suppressive microenvironments. We discuss these approaches across infections, including human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV); autoimmunity involving CD19- and B-cell maturation antigen (BCMA)-directed depletion strategies and CAR-engineered regulatory T cells (CAR-Tregs); fibrosis targeting fibroblast activation protein (FAP); hemophilia using B-cell antibody receptor (BAR)-CARs against factor VIII and factor IX inhibitors; transplantation employing human leukocyte antigen (HLA)-specific CAR-Tregs; and senescence-associated pathologies targeting urokinase plasminogen activator receptor (uPAR) and natural killer group 2D ligands (NKG2DLs). Early clinical experiences in systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis, together with preclinical successes in chronic infections and fibrotic disease, demonstrate both feasibility and durable disease modification. By extending CAR-T therapy beyond oncology, these applications position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.

γδ T cells represent a promising avenue for cancer immunotherapy. The Vγ9Vδ2 T-cell receptor (TCR), which is expressed by the predominant subset of γδ T cells, responds to phosphoantigen (pAg)-engaged butyrophilins (BTNs) on various cancer cells. However, the molecular mechanism underlying the pAg-mediated activation of Vγ9Vδ2 TCRs remains a subject of debate. Here, we employed an integrative approach to elucidate the mechanism of pAg reactivity in Vγ9Vδ2 T cells. Our results demonstrate that BTNs form higher-order oligomers in the absence of pAg. Upon pAg binding, these higher-order oligomers dissociate into separate tetramers, enabling Vγ9Vδ2 TCR engagement. This pAg-induced dissociation of higher-order BTN oligomers is critical for pAg-mediated activation of γδ T cells. Our findings reveal a mechanism of BTN higher-order oligomer dissociation-driven pAg sensing, providing valuable insight for future immunotherapeutic strategies.

Hypoxia, a hallmark of solid tumors, poses a significant challenge in cancer therapy due to its association with poor prognosis and resistance to conventional treatments. Oncolytic viruses represent a promising treatment strategy, as they selectively replicate within cancer cells and lyse them, potentially including those in hypoxic tumor regions. Here, we examined how hypoxic conditions influence the activity of enadenotucirev (EnAd), a clinically relevant group B oncolytic adenovirus previously detected in hypoxic areas of xenograft tumors. We demonstrated that hypoxia enhances virus production by boosting transcription and translation of immediate-early, early, and late adenoviral genes. The immediate-early gene E1A was upregulated within 2 h (17-fold) after virus entry under hypoxia, driven by a conserved hypoxia-response element (HRE) in its promoter. Mechanistic studies revealed that the hypoxia-inducible factor (HIF)-2α and HIF-1β heterodimers bind to this HRE, transactivating E1A. By inducing E1A expression, hypoxia also elevated viral genome synthesis, structural protein production, and therapeutic transgene expression, underscoring the potential of EnAd to target the hypoxic tumor microenvironment. This is the first report of a functional HRE in a human adenovirus, conserved across 59 adenovirus genotypes, and identifies hypoxia as a driver of enhanced oncolytic activity with implications for adenovirus-based therapies in solid tumors.

Single-cell transcriptomics identifies a convergent activation state of conventional dendritic cells (cDCs) shared by type 1 and type 2 cDCs (cDC1s and cDC2s). These activated DCs (actDCs) are characterized by co-expression of T cell-stimulating and inhibitory molecules. Here, we examined the functional contribution of actDCs to anti-tumor immunity by developing mouse models that leverage CCR7 expression to conditionally label or ablate actDCs. The capacity of cDCs to stimulate tumor-specific cytotoxic T lymphocytes (CTLs) was restricted to the actDC state. cDC1- and cDC2-derived actDCs supported CTL priming through cross-presentation and cross-dressing, respectively, with the latter occurring in a cancer type-dependent manner. actDCs were required for the activation of naive CTLs in tumor-draining lymph nodes and for sustaining effector CTL function within tumors. Consequently, ablation of actDCs impaired spontaneous tumor control and responses to immune checkpoint blockade or adoptive T cell therapy. Thus, the actDC state emerges as a critical determinant of cDC-mediated anti-tumor immunity.

Bile acids have emerged as compartmentalized immunometabolic signals that link host metabolism, microbial ecology, and tumor immunity. Altered bile acid profiles are common across malignancies and are associated with tumor progression, immune tone, and responsiveness to immunotherapy. Bile acids shape the gut microbiota, and in turn, microbial enzymes diversify the bile acid pool, generating distinct bile acid species that can remodel the tumor immune landscape. Depending on species identity, concentration, and context, bile acids can support immune surveillance or enforce immune escape by reshaping antigen priming, lymphocyte fitness, myeloid suppression, and immune cell trafficking. Here, we synthesize emerging concepts defining a microbiome-bile acid-immune axis in cancer and highlight therapeutic opportunities to harness bile acid signaling as next-generation strategies in oncology.

Cancer vaccines have underperformed clinically, largely because antigen-specific CTL priming and expansion are constrained by insufficient costimulatory activation and increased DC-mediated coinhibition. Here, we present a personalized cancer vaccine platform, STAR, which engineers stimulator of interferon gene (STING)-activating autologous tumor-derived microvesicles (TMVs) to concurrently amplify costimulatory signaling and relieve DC coinhibition during antigen cross-presentation. TMVs provide broad tumor antigen cargo and intrinsic STING activity; loading manganese phosphate nanoparticles (MnPs) potentiates cGAS-STING signaling, drives DC maturation, and enhances antigen cross-presentation. Importantly, concurrent delivery of PD-L1-targeting siRNA (siPD-L1) effectively inhibits DC-associated PD-L1, freeing CD80 to engage CD28 and limiting PD-1/PD-L1 signaling and thereby significantly enhancing antigen-specific CD8+ T cells. In mouse models, STAR vaccination elicited durable prophylactic immunity and achieved substantial therapeutic efficacy against melanoma and colorectal tumors without additional immunotherapies. Notably, patient-specific STAR vaccines derived from surgically resected tumors effectively prevented postoperative recurrence and metastasis in aggressive melanoma and triple-negative breast cancer models, thereby highlighting their translational potential. Overall, the STAR vaccine platform offers a versatile and clinically applicable approach to enhancing personalized cancer immunotherapy across diverse cancer types.

Toll-like receptors (TLRs) are considered general sensors of bacterial encounters. Here, we examined whether other pattern recognition receptors are commonly activated during bacterial infection. TLR-independent interferon (IFN) responses were induced in macrophages in response to diverse bacterial encounters. Of the cytoplasmic receptor families examined, the cyclic dinucleotide (CDN) sensor STING was required for IFN responses to evolutionarily diverse bacteria. Various bacterial CDNs were present in murine tissues; these activated stimulator of interferon genes (STING) after bacteriolysis in phagolysosomes in a manner requiring two CDN transporters. Importantly, bacterial CDNs were increased in colonic biopsies from patients with inflammatory bowel disease. Systemic delivery of dead, CDN-laden bacteria promoted anti-tumor immunity in mice. Detection of diverse CDNs, including pyrimidine-based CDNs, was an evolutionarily conserved feature of STING, with distinct binding modes for purine- and pyrimidine-based CDNs. Thus, a phagocytosis-CDN-STING connection places cytoplasmic sensing as a common outcome of host-bacteria interactions that set the immune tone of a tissue, with implications for host defense.

Gut microbial metabolites play crucial roles in regulating systemic immunity, but their mechanisms and limited drug-like properties remain unresolved. Here we report an oral nano-formulation that leverages gut microbial metabolites to modulate T cell metabolism and amplify antitumour immunity. Through an in vitro screening of gut microbial metabolites, we identified 3,4-dihydroxybenzoic acid that improved adoptive T cell therapy and enhanced CD8+ T cell stemness by suppressing glycolysis and regulating the Akt-mTORC1-Myc pathway. To harness the potency of 3,4-dihydroxybenzoic acid for systemic cancer immunotherapy, we engineered a 3,4-dihydroxybenzoic acid prodrug nano-emulsion, significantly increasing its oral absorption and half-life. In multiple murine tumour models, the oral nano-emulsion enhanced the expansion of antigen-specific, stem-like CD8+ T cells, sensitizing tumours to anti-PD-1 blockade and exerting robust antitumour efficacy. By integrating nanotechnology with microbial-metabolite-based immunotherapy, this study establishes a mechanistic link between the gut microbiota and T cell immunity, offering a promising approach for cancer immunotherapy.

Women who carry a pregnancy to term have long been known to have a reduced lifetime risk of breast cancer, yet the mechanisms underlying this protection remain poorly understood. While parity-induced differentiation and hormonal remodeling of mammary epithelium have been considered primary drivers of breast cancer protection, the contribution of immune adaptation has remained largely unexplored. In a recent issue of Nature Immunology, Hussain and colleagues identify pregnancy-induced tissue-resident memory-like (TRM-like) CD8⁺ T cells as key mediators of parity-associated breast cancer protection. The authors show that pregnancy establishes a nurturing niche in the mammary gland that supports the expansion of TRM-like cells through epithelial-derived IL-15 and TGF-β, and that depletion of these cells abolishes the cancer-protective effect of parity. Moreover, using therapeutic agents to enhance IL-2Rβ signaling was sufficient to induce expansion of breast cancer-protective TRM-like cells in nulliparous mice, raising the possibility that pregnancy's protective imprint could be pharmacologically induced. Given the established link between TRM cells and immune checkpoint blockade responsiveness in breast cancer, these findings also raise the possibility that pregnancy-induced TRM-like populations could be leveraged to improve immunotherapy outcomes. By linking physiological developmental tissue remodeling to durable local immunosurveillance, this study expands current concepts of tissue-resident immunity and positions pregnancy as an immune-educating event with lasting consequences for breast cancer susceptibility.

Tertiary lymphoid structures (TLSs) correlate with favorable responses to immune checkpoint inhibitors (ICIs) in various cancers, yet many patients with TLS-positive tumors are resistant to treatment. Multi-omic profiling of clear cell renal cell carcinoma (ccRCC) and soft tissue sarcoma tumors (STSs) reveals an upregulation of gamma-aminobutyric acid (GABA)-related signatures in non-responders to ICIs. In ccRCC, TLSs from non-responders located near GABA-producing tumor cells exhibit impaired B cell maturation, reduced IgG production, higher GABA receptor expression, and tricarboxylic acid cycle activation. In vitro, exposure of human B cells to GABA reduces HLA-DR expression, proliferation, and immunoglobulin secretion by receptor-independent and dependent mechanisms. Pharmacological inhibition of GABA-synthesis increases ICI response and immune infiltration, particularly by B cells, in a TLS-positive STS mouse model. Our findings unravel GABA as an immunoregulatory metabolite and provide a rationale for its therapeutic targeting to overcome ICI resistance in patients with TLS-positive tumors.

In this issue of Cancer Cell, Hernández-Verdin et al. reveal why some tumors with tertiary lymphoid structures (TLSs) resist immunotherapy: their findings identify cancer-derived gamma-aminobutyric acid (GABA) as an immunosuppressant factor resulting in dysfunctional TLS and immunotherapy resistance. Targeting GABA with immunotherapy reshapes the tumor and TLS microenvironment and ultimately improves therapeutic efficacy.

Bispecific antibodies (BsAbs), designed to recognize two different antigens or two different epitopes on the same antigen, are generated in laboratories using various techniques, including chemical conjugation (introduced in the 1960s), cell fusion (introduced in the 1980s), and protein engineering (first introduced around the 1990s). The activity of BsAbs is dependent on how the two co-targets are strategically selected; BsAbs can be designed to redirect immune cells or block signaling pathways and to deliver therapeutic activities spatiotemporally to where they are needed. BsAbs are revolutionizing treatment of cancer and other diseases. As of this writing, at the beginning of 2026, 16 BsAbs and 1 BsAb-like fusion protein are approved in the US and/or China, of which 15 are for cancer treatment and 2 are for non-cancer indications, and many more BsAbs are in clinical trials. Next-generation BsAb development is transitioning from traditional wet-lab approaches to artificial intelligence (AI)-powered platforms. AI-assisted tools are poised to facilitate the identification of new targets, predict protein structures, and guide the development of promising new BsAb formats for the treatment of cancer and other diseases.

Cell-Cell adhesion maintained by tight junctions (TJs) is essential for epithelial integrity; loss of TJs correlates with poor prognosis, metastasis, and adverse clinical outcome in gastric cancer (GC). Restoring TJ integrity is therefore considered a promising therapeutic strategy in GC. The study identifies the stomach renin angiotensin system (stRAS) as a crucial regulator of TJ function in GC. Using integrative analysis of GC patient tissues, human GC cell lines, and orthotopic GC xenograft models, here we show that angiotensin II (ATII), the principal effector peptide of stRAS, drives TJ disassembly through an autocrine loop involving angiotensin receptor type 1 (AT1R) expressed on GC cells. Both ATII and AT1R are overexpressed in GC, where they suppress the expression of key TJ proteins. By analyzing global RNA-sequencing (RNA-seq) data and performing CRISPR/Cas9 gene deletion, chromatin immunoprecipitation, and functional assays, we mechanistically reveal that ATII, which is predominantly produced by cancer cells within the tumor microenvironment (TME), inhibits the expression of krüppel-like factor 4 (KLF4), a transcription factor crucial for the transcription of key TJ genes (CLDN1, 3, 4, and TJP1), leading to reduced synthesis of TJ proteins via AT1R expressed on cancer cells. Notably, the study demonstrates the effectiveness of pharmacological inhibition of AT1R with clinically established AT1R antagonists in preventing GC growth and metastasis by restoring TJ stability in vivo. These findings delineate a previously unrecognized role for ATII in governing TJ disassembly in GC and highlight the ATII/AT1R axis as a promising therapeutic target.

: The glioblastoma (GBM) immunosuppressive tumor microenvironment is a clinical challenge. Oncolytic Zika virus (ZIKV) has emerged as a promising therapy, targeting treatment-resistant glioma stem cells, stimulating CD8+ T-cell-mediated immunity and extends survival in preclinical models but myeloid cell-driven immunosuppression persists. An antagonist of Siglec-15, a myeloid immune checkpoint molecule, is in a phase II trial for non-small cell lung cancer, but its role in CNS malignancies remains unclear. : We evaluated Siglec-15 expression in human GBM samples using flow cytometry, mass cytometry, and immunofluorescence, as well as a public database. Using syngeneic glioma models, we tested a blocking antibody against Siglec-15, and Siglec-15 knock out mice, alongside ZIKV and anti-PD-1 therapies. We performed survival studies and analyzed immune responses, T-cell proliferation and phagocytosis, and tumor rechallenge. : Siglec-15 was expressed by human GBM myeloid (16-22%) and tumor (18-19%) cells, and higher expression was associated with shorter survival. In CT2A-bearing mice, ZIKV + anti-Siglec-15 increased long-term survival to 60% (vs. 40% with ZIKV alone), rising to 83% with anti-PD-1 treatment. Triple therapy in SB28 bearing mice yielded 76% long-term survivor rate with 1.7-fold higher CD8+ T-cell activation. Rechallenged mice showed 11-fold expansion of brain resident/effector memory CD8+ T-cells and 80% survival. Siglec-15 loss on myeloid cells enhanced phagocytosis (CT2A: 25%; SB28: 7%) and T-cell responses (activation: 81%; proliferation: 86.8%). : Targeting Siglec-15, combined with PD-1 blockade and ZIKV overcomes myeloid immunosuppression and enhances T-cell activation in GBM, promoting durable anti-tumor immunity. These findings support further investigation of this combination therapy.

Recent advances in cancer immunotherapy face challenges such as limited efficacy in solid tumors, adverse effects, and prohibitive costs. This study addresses these challenges by developing a theranostic magnetic nanocomposite (mNC) system for on-demand delivery of small-molecule immunomodulating drugs (smIDs) to solid tumors. This system enables externally triggered drug release under alternating magnetic fields (AMFs) and simultaneous MRI monitoring. Functionalization with a granzyme B (GzmB)-responsive fluorescent probe allows real-time assessment of immune activation, focusing on NK cells and CTLs. In vitro and ex vivo validation demonstrated effective mobilization of innate and adaptive immune responses, resulting in approximately 60% tumor cell viability reduction correlating with GzmB activity and increased cytokine release. Validation further demonstrated the ability of the system to report tumor accumulation (via MRI) and immune cell activation (optical imaging). This platform offers precise spatio-temporal control of immunotherapy delivery combined with noninvasive imaging and immune response monitoring, representing a promising strategy for enhancing the specificity and efficacy of cancer immunotherapies.

Clinical translation of sonodynamic therapy for hepatocellular carcinoma is limited by a safety-efficacy paradox: sonosensitizer activation in healthy tissues poses risks, while tumor efficacy is constrained by hypoxia and redundant antioxidant defenses. To resolve this, dual-switchable core-shell nanoparticles were engineered. Under physiological conditions, a carboxymethyl chitosan shell and a peptide radical scavenger keep the nanoparticles inert, ensuring systemic safety. In the acidic tumor microenvironment, the shell disassembles, and ultrasound exposure triggers a coordinated therapeutic cascade. The linear dumbbell‑shaped piezoelectric core, barium titanate‑gold‑barium titanate heterojunction, generates oxygen, alleviating tumor hypoxia, and simultaneously produces oxyradicals, enabled by a record piezopotential of 4.12 V and its inherent direct water‑splitting capability. Two inhibitors are released to block the AMP‑activated protein kinase and nuclear factor erythroid two-related factor 2 antioxidant pathways, disabling cellular defenses and amplifying oxidative damage. This integrated strategy induces ferroptosis, mitochondrial dysfunction, DNA damage, and immunogenic cell death, as validated by physicochemical characterization, multi-omics, and in vivo studies. In subcutaneous tumor models, inhibition rates reached 98.7% in immunocompetent mice and 91.9% in T‑cell‑deficient mice, with excellent safety. This work establishes a therapeutic paradigm reconciling systemic safety with potency, offering a translatable strategy for HCC.

Small-cell lung cancer (SCLC) is widely considered one of the most aggressive human malignancies, characterized by development of rapid metastases and eventual resistance to platinum chemotherapy and immunotherapy. For decades, despite rigorous scientific investigation and well-established mouse models providing a basis for mechanistic understanding, there were limited therapeutic advances for SCLC. The past decade has seen reinvigoration of drug development for SCLC as well as US Food and Drug Administration (FDA) approval of tarlatamab, a bispecific T-cell engager with unprecedented survival advantage in this recalcitrant disease. Multiple other promising clinical trials in the first and later-line settings are underway that seek to challenge standards of first-line chemoimmunotherapy, investigate combination treatments in the later line, and introduce T-cell engagers earlier in treatment. This review provides a comprehensive primer on the biology and molecular landscape of SCLC, in the context of how both shape ongoing investigational strategies. A broad overview of established multidisciplinary management of both limited-stage and extensive-stage SCLC is discussed to provide understanding of how the next decade is likely to bring significant clinical gains as emerging therapeutics seek to redefine the management of SCLC and build upon novel advances.

Clear cell renal cell carcinoma (ccRCC), the most common renal cancer, is largely driven by von Hippel Lindau (VHL) protein deficiency. VHL inactivation promotes epithelial-to-mesenchymal transition (EMT), invasion, and hypervascularization, through vascular endothelial growth factor (VEGF) signaling, resulting in an abnormally complex vasculature. Given the limited prognostic value of microvessel density and the frequent development of resistance to VEGF-targeted therapies, the architecture of the ccRCC vascular network is likely a critical, underexplored determinant of therapeutic response. This study investigates the three-dimensional (3D) architecture of ccRCC vasculature within the tumor microenvironment and its response to drugs. Examination of human ccRCC samples revealed two vascular structures, designated ponds and sheets, that are morphologically distinct from tumor capillaries. High-resolution 3D imaging of optically cleared patient-derived xenografts revealed that ponds formed large, irregular structures with wide luminal cavity, whereas sheets were thin, elongated, and collapsed. We engineered a 3D in vitro tumor spheroid-endothelial cell co-culture model, incorporating EMT-like tumor spheroids co-cultured with endothelial cells, that mimicked pond architecture. Time-lapse imaging revealed a temporal link between tumor invasion and pond morphogenesis. Drug testing demonstrated that temsirolimus, crizotinib, and sunitinib impaired capillary morphogenesis and tumor invasion to varying extents in monoculture, while co-culture model reduced overall drug efficacy. Importantly, ponds exhibited markedly reduced sensitivity to sunitinib compared with adjacent capillaries, suggesting that they may contribute to anti-angiogenic resistance. This study defines key features and heterogeneity of ccRCC vascular architecture and highlights ponds as candidate contributors to treatment failure and targets for future interventions.

Gastric adenocarcinoma (GAC) remains a leading cause of cancer-related mortality, particularly in patients with peritoneal carcinomatosis, for whom effective therapies are limited. We investigated the therapeutic efficacy and molecular mechanism of CYD-4-61, a BAX activator, using human GAC cell lines, patient-derived xenograft models, genetically engineered mouse models, and a syngeneic mouse model. CYD-4-61 potently inhibited tumor cell proliferation, induced apoptosis, and suppressed cancer stem cell-like properties, with enhanced activity in radiation-resistant GAC cells. Mechanistically, CYD-4-61 activated the BAX-caspase pathway, leading to SOX9 protein reduction. Integrated bulk and single-cell transcriptomic analyses identified SOX9-dependent transcriptional programs as major targets of CYD-4-61. Functional rescue experiments together with chromatin immunoprecipitation and CUT&RUN analyses supported CDK4 as a SOX9-regulated gene and demonstrated suppression of the SOX9-CDK4 regulatory axis following CYD-4-61 treatment. In multiple preclinical models, CYD-4-61 significantly inhibited tumor growth and improved the therapeutic response to anti-programmed cell death protein 1 (PD-1) therapy while modulating the tumor immune microenvironment. Clinically, co-expression of SOX9 and CDK4 was associated with diffuse-type GAC and poor patient outcomes. These findings identify the BAX-SOX9-CDK4 axis as an important mechanism contributing to the antitumor activity of CYD-4-61 and provide a strong preclinical rationale for its further development as a therapeutic strategy for aggressive GAC.

Altered glucose metabolism is an auspicious feature of solid tumors, but is it an intrinsic property of tumor cells or a metabolic adaptation to the tumor microenvironment? Using normal epithelial cells cultured in a physiological culture medium under conditions that mimic the physical properties of healthy or cancerous tissues, we establish multiomics relationships between the biochemical and physical properties of the microenvironment and its impact on biosynthetic outputs of altered glucose metabolism. We find that microenvironmental properties, such as hyperglycemia, can affect the composition and thickness of the epithelial glycocalyx, in part through the activity of mechanosensitive stress responses associated with Heat Shock Factor 1 (HSF1). Because glycocalyx thickness alters immune surveillance of epithelial-origin tumor cells, we examined the relationship between the HSF1-hyperglycemia axis in human breast tumors and validate it as a druggable vulnerability to license natural killer cell lethality against cancer cells.

Mitochondria activate immunity, but the role in cancer is unknown. Here, we report that transgenic expression of Parkin, a regulator of mitochondrial fitness, induces inflammation and interferon (IFN) gene signatures, suppresses prostate cancer formation and generates CD8+ and CD20+ intraprostatic immune aggregates. These had hallmarks of mature tertiary lymphoid structures (TLS), expressing markers of B cell maturation (CXCL13, CCL21), germinal center formation (BCL6, GL7), mature dendritic cells (MHC-II/CD208) and high endothelial venules (LYVE-1). Parkin TLS showed high Ig gene expression, recruitment of CXCR5+ follicular T helper cells and expansion of CD69+/KLRG1+ effector T cells. Conditioned medium from Parkin-positive cells expanded memory B and plasma cells, increased IgG1 production, and sustained B and T cell migration. Finally, conditional expression of Parkin induced TLS formation, upregulated Ig chains and inhibited prostate cancer growth, in vivo, whereas Parkin reconstitution in IFNAR1, CD8 or CD20 knockout mice had no effect. Therefore, mitochondrial immunity orchestrates antitumor responses, and TLS formation contributes to tumor suppression.

Tumor immune barriers (TIBs) are spatially organized stromal-immune niches that restrict lymphocyte entry. To explain persistent immune-checkpoint blockade (ICB) resistance in clear cell renal cell carcinoma (ccRCC), we mapped TIBs and defined a peritumoral variant built from POSTN+ cancer-associated fibroblasts (CAFs) interlaced with APOE+ tumor-associated macrophages (TAMs). This niche excluded CD8+ T cells from tumor cores, and was enriched in poor-prognosis, ICB-refractory patients. Spatial transcriptomics and single-cell profiling showed TIB regions enriched for extracellular-matrix remodeling, immunosuppressive ligand-receptor circuits, and metabolic reprogramming. Mechanistically, tumor-derived TGF-β1 activated CAFs via SMAD signaling, inducing POSTN and recruiting APOE+TAMs through integrin and chemokine axes. TAMs secreted TGF-β1 and VEGFA, amplifying stromal programs and sustaining exclusion. Blocking POSTN reprogrammed macrophages, reduced matrix-mediated suppression, and restored CD8+ infiltration. In vivo, POSTN inhibition combined with ICB boosted antitumor immunity, reduced tumor burden, and reversed immunosuppressive infiltration, nominating POSTN-directed strategies to potentiate ICB.

Adoptive T cell therapy requires T cells to infiltrate vascular tissues and preserve immune function. In solid tumor treatment, however, the surrounding microenvironment produces abnormal vasculature that impedes T cell infiltration. An approach that enables vascular normalization and enhances adoptive T cell function in parallel is essential for effective therapy but has not been reported. Here, we report the use of lenvatinib (LEN) to induce transient vascular normalization, thereby facilitating T cell infiltration. Moreover, LEN enhances T cell persistence by promoting the differentiation of T cells toward a memory phenotype. Our results indicate that the differentiation is by suppressing the PI3K-AKT-mTOR pathway, which drives effector differentiation, and by activating FOXO1, a transcription factor that promotes memory formation. To coordinate the transient vascular normalization and T cell enhancement, we link LEN-loaded, PD-L1-blocking micelles to T cells through acid-labile click chemistry, forming pH-responsive T cell-nanodrug conjugates. The conjugates synchronize the intratumoral release of LEN and the PD-L1 antagonist peptide OPBP-1, thereby coordinating vascular normalization, T cell differentiation, and checkpoint blockade. In vivo, the conjugates increased intratumoral CD8+ T cells and splenic memory T cells by over sixfold in B16-OVA tumors and achieved complete regression in a subset of MC38-OVA tumors without systemic toxicity, providing a promising strategy for solid tumor immunotherapy.

Neutrophils are increasingly recognized as key orchestrators of the immunosuppressive tumor microenvironment, yet their intrinsic plasticity, short lifespan and resistance to genetic manipulation have impeded therapeutic targeting. Here, we report a non-pharmacological, biophysical immunomodulatory strategy based on cold atmospheric plasma (CAP) to reprogram tumor-associated neutrophils and restore antitumor immunity. We show that CAP simultaneously delivers reactive oxygen species and redox cues that inhibit mitophagy, thereby restoring mitochondrial membrane potential and oxidative metabolism in neutrophils. This metabolic reinstatement drives a shift from immunosuppressive to immunostimulatory phenotypes. In both syngeneic and humanized bladder cancer models, intravesical CAP reshapes the myeloid landscape, enhances T cell infiltration, suppresses tumor progression, and sensitizes tumors to PD-1 blockade. These findings establish CAP as a locoregional, drug-free biophysical modality capable of overcoming neutrophil-mediated immune suppression and provide a materials-based framework for modulating innate immunity in solid tumors.

Organ-selective immunomodulation is increasingly viewed as a route to improve the therapeutic index of cancer immunotherapy, yet most agents are still delivered systemically, where limited tumor exposure and immune-related toxicities remain common. The lung is an attractive site for local intervention because it is directly accessible and immunologically specialized. However, effective pulmonary delivery is constrained by mucociliary clearance, airway mucus, alveolar macrophage uptake, and epithelial barriers. Nanomaterials can be rationally engineered to address these constraints, increasing pulmonary retention and concentrating immunotherapeutics within the lung tumor microenvironment while reducing systemic burden. This Review summarized the key physiological barriers for pulmonary immunotherapeutic delivery and discusses how nanomaterial properties shape deposition, retention, cellular partitioning, and downstream immune activation. We critically evaluate representative inhalable platforms across major immunotherapeutic modalities, including vaccines, immune checkpoint blockade, innate immune agonists (e.g., STING agonists), cytokine regulation, and emerging in situ immune-cell engineering strategies. We also highlight translational considerations. Together, these advances support inhalable immunotherapeutic nanomedicines as a complementary approach to current lung cancer treatment and a broader framework for pulmonary immune modulation.

The human gut microbiota constitutes the largest and most metabolically active microbial ecosystem in the body, and accumulating evidence links dynamic alterations in microbial composition and function to the initiation, progression, and treatment responses of multiple gastrointestinal (GI) cancers, including esophageal, gastric, hepatocellular, pancreatic, and colorectal malignancies. This review synthesizes current evidence on dysbiosis signatures, mechanistic pathways, and translational opportunities across major GI cancer types, with a focus on microbe-derived metabolites and microbe-associated molecular patterns that shape inflammation, epithelial barrier integrity, and antitumor immunity. Across GI cancers, recurrent patterns include enrichment of pro-inflammatory/pathobiont taxa, depletion of homeostasis-maintaining and butyrate-producing commensals, and perturbations in metabolic axes centered on bile acids and short-chain fatty acids. Mechanistically, these changes can remodel the tumor microenvironment via epithelial and immune signaling, epigenetic regulation, and metabolic reprogramming. Importantly, the gut microbiota is increasingly recognized as a modifiable determinant of the efficacy and toxicity of immune checkpoint blockade, adoptive cell therapies, chemotherapy, and radiotherapy. Despite rapid advances, key challenges persist in translating microbiome research into cancer care, including validation, standardization, variability, and safety. Future success likely depends on function-oriented, targeted modulation, supported by multi-omics, strong causal evidence, and clinical trials.

Though inhibiting the RBPJ transcription complex reduces PD-L1 expression and alleviates T cell dysfunction in hepatocellular carcinoma (HCC), the tumor immunomodulatory function of RBPJ in T cells is unclear. This study used patient-derived xenograft models to illustrate the role of RBPJ disruption in clinical outcomes and sensitivity to immunotherapy. Immunoprecipitation was performed to identify whether HUWE1 is the E3 ubiquitin ligase for RBPJ. CUT&Tag, ChIP-/ATAC-qPCR, flow cytometry, and CyTOF were used to investigate the molecular mechanism of how RBPJ regulated the function of HCC-infiltrating T cells. Mice with conditional knockout or knock-in of Huwe1 or Rbpj in T cells were used to evaluate their role in the tumor growth. Furthermore, virtual screening, molecular dynamics simulation, immunoprecipitation, and DNA pull-down assays revealed the role of acarbose in RBPJ transcription complex. Our study found that RBPJ expression rose in exhausted T cells, aggravating their exhaustion. Mechanistically, HUWE1 facilitated the K341 ubiquitination of RBPJ through K48 linkage. RBPJ contributed to T cell exhaustion by enhancing the transcription of exhaustion-related genes as a transcription factor, recruiting RUVBL1 to elevate H3K4me3 levels on the promoters of exhaustion-related genes or H3K27ac on their enhancers, and induced the transcription of the KMT2C, thereby increasing H3K4me1 levels on the enhancers of exhaustion-related genes. Furthermore, acarbose-induced damage in the RBPJ transcriptional complex indicated that targeting T cell exhaustion may be a promising HCC treatment. Collectively, our research results indicated that inhibiting the RBPJ in T cells changed the tumor microenvironment from "cold" to "hot".

Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m⁶A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter. Comprehensive analyses included m⁶A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and transforming growth factor-β signaling. METTL3 also promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting the clinical development of METTL3 inhibitors for ACC treatment.

The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined. Streptococcus anginosus enrichment was assessed in ICB-unresponsive GC tissues from patients and multiple preclinical models. Orthotopic, subcutaneous, and germ-free mono-colonized mouse models were employed to evaluate the impact of S. anginosus on antitumor immunity and programmed cell death protein 1 (PD-1) blockade efficacy. Integrated multi-omics analyses were performed to identify microbiota-derived metabolites, and mechanistic studies investigated their effects on CD8+ T-cell function. Therapeutic targeting of integrin α2 (ITGA2) was tested to assess restoration of cytotoxic T-cell activity and sensitization to PD-1 blockade. S. anginosus was markedly enriched in ICB-non-responsive GC tissues. Colonization with S. anginosus impaired antitumor immunity and promoted PD-1 blockade resistance by suppressing CD8+ T-cell effector function. Multi-omics analyses identified kynurenic acid (KA) as a microbiota-derived metabolite selectively enriched following S. anginosus colonization. KA induced ITGA2 expression and inhibited an mTOR-dependent signaling cascade, sustaining cathepsin V expression and attenuating interferon-γ and granzyme B production in CD8+ T cells. Therapeutic inhibition of ITGA2 restored CD8+ T-cell cytotoxicity and sensitized tumors to PD-1 blockade. A microbiota-metabolite-immune signaling axis involving S. anginosus, KA, and ITGA2 drives immunotherapy resistance in GC. Therapeutic inhibition of ITGA2 represents a potential strategy to overcome ICB resistance in GC.

Immune checkpoint blockade (ICB) therapy has emerged as a pivotal cancer treatment by activating antitumor immunity. However, its clinical efficacy remains limited in many patients, highlighting the need for combination strategies to overcome resistance. Inducing immunogenic cell death (ICD) represents a promising approach to remodel the immunosuppressive tumor microenvironment and improve ICB efficacy. A high-throughput screen of a natural compound library identified potent ICD inducers. Polyphyllin II (PPII), a bioactive component from Paris polyphylla, was selected for further investigation. Its effects on ICD markers, tumor growth, and immune activation were evaluated in vitro and in vivo. Limited proteolysis-mass spectrometry was employed to identify the direct target of PPII, followed by mechanistic studies using molecular and immunological assays. PPII was identified as a potent ICD inducer, stimulating the release of high mobility group box 1, ATP, and calreticulin from tumor cells. PPII suppressed tumor growth and enhanced antitumor immunity by promoting dendritic cell maturation and antigen cross-presentation, leading to CD8+ T-cell activation. Mechanistically, PPII directly bound to glucose-regulated protein 75 (GRP75), enhancing endoplasmic reticulum-mitochondrial tethering, provoking endoplasmic reticulum stress and mitochondrial calcium overload, and promoting cytochrome c release and caspase-3 activation. This cascade ultimately triggered gasdermin E (GSDME)-mediated pyroptosis. Furthermore, PPII synergized with anti-programmed cell death protein 1 therapy by reprogramming the tumor immune microenvironment and promoting systemic antitumor immunity. Our findings identify GRP75 as a novel therapeutic target for cancer immunotherapy and highlight PPII-driven immune reprogramming as a translatable strategy to potentiate ICB efficacy through the induction of immunogenic pyroptosis.

Antibody-drug conjugates (ADCs) show clinical efficacy against several solid malignancies, inducing cytotoxic effects in malignant cells accompanied by changes in the composition of the tumor stroma. The therapeutic effects of some ADCs have been shown to be potentiated by combination with anti-PD(L)1 checkpoint inhibitors, highlighting the potential of combining ADCs and immunotherapy. Here, we investigated the potential of combining ADCs with agonist monoclonal antibodies targeting CD137 (4-1BB), a costimulatory receptor expressed on antigen-primed T lymphocytes and activated NK cells. The combination of MMAE- and deruxtecan-conjugated ADCs towards NECTIN-4 or HER2 with anti-CD137 agonists elicited synergistic effects in mouse tumor models. Treatment with the ADCs increased CD137 expression on intratumor CD8+ and CD4+ T lymphocytes. Moreover, the synergistic antitumor therapeutic efficacy was dependent on cDC1 dendritic cells and CD8+ T cells. ADCs induced features of immunogenic cell death in malignant cells, resulting in cross-presentation and maturation of cDC1 dendritic cells that cross-prime CD8+ T cells to become CD137-positive. Importantly, the anti-CD137 plus ADC synergistic combination attained efficacy against concomitant tumor lesions that failed to express the ADC target. Together, these findings demonstrate that anti-CD137 agonists hold promise for combination strategies with ADCs.

Esophageal squamous cell carcinoma (ESCC) exhibits heterogeneous responses to immune checkpoint blockade, highlighting the need to define tumor-intrinsic mechanisms driving resistance to PD-L1 inhibition. Here, we identified GTP-binding protein overexpressed in skeletal muscle (GEM) as a tumor cell-intrinsic regulator associated with poor response to anti-PD-L1 therapy in ESCC. GEM expression in tumor cells drove tumor-associated macrophage (TAM)-mediated immunosuppression, leading to reduced CD8⁺ T cell infiltration and impaired cytotoxic function. Mechanistically, GEM induced SERPINE1 expression that was secreted and acted on macrophage LRP1 to drive alternative activation and suppress antitumor immunity. GEM enhanced SERPINE1 expression through a MKK3-RACK1-p38-MEF2A cascade. GEM signaling was reinforced by a metabolically coupled feedback mechanism. Macrophages exposed to GEM-high tumor cells promoted tumor cell glycolysis and lactate production, which drove AARS1-dependent lactylation of GEM and strengthened its interaction with RACK1 to amplify downstream signaling. Disruption of the SERPINE1-LRP1 axis restored CD8⁺ T cell activity and enhanced response to PD-L1 blockade in vivo. Pharmacological perturbation of GEM-dependent signaling remodeled the tumor immune microenvironment and improved responses to PD-L1 blockade. Together, these findings define a GEM-SERPINE1-LRP1 signaling axis that drives macrophage-mediated immune suppression and suggest that targeting this pathway may enhance the efficacy of PD-L1 blockade in ESCC.

Prostate cancer (PCa) is one of the most common cancers in males, and its treatment remains challenging due to the tumor microenvironment (TME) with immunosuppressive properties and limited response to anti-PD-1 therapy. Gut microbiota-derived metabolites have recently emerged as modulators of cancer immunometabolism, however, their role in PCa progression and immunotherapy is poorly understood. Here we found that indole-3-lactic acid (ILA), a metabolite produced by Lactobacillus plantarum, exerted dual anti-tumor effects on PCa cells and the TME. Mechanistically, ILA activates the aryl hydrocarbon receptor (AHR), and the resulting AHR/ARNT heterodimer translocates into the nucleus and binds to the promoter of ASF1B. This heterodimer then recruits the HDAC1/2-NuRD complex to reduce H3K27ac levels and suppress ASF1B expression. ASF1B binds to specific residues of ENO1 via its N-terminal core domain and enhances ENO1 enzymatic activity. ILA-induced downregulation of ASF1B impairs this interaction, reduces ENO1 activity, and suppresses the PI3K/Akt pathway, thereby inhibiting the malignant phenotypes of PCa cells. Concurrently, ILA decreased CXCL8 secretion by inhibiting the PI3K/Akt/NF-κB pathway, enhancing CD8+ T cell infiltration and M1 macrophage polarization, thereby remodeling the TME. Additionally, ILA synergized with anti-PD-1 therapy to more effectively suppress tumor growth. These findings reveal a novel mechanism by which gut microbiota-derived metabolites regulate PCa progression and immunometabolism, positioning ILA as a potential therapeutic agent to improve PCa treatment.

Transcription blockage frequently occurs in tumor cells, and aberrant R-loop formation during this process drives genome instability. However, the regulation of R-loop homeostasis and its contribution to tumorigenesis remain to be investigated. Here, we report that the RNA exonuclease REXO4 resolves R-loops by 3'-5' exonucleolytic cleavage of the RNA strand within RNA-DNA hybrids. Accessible RNA ends, generated by endonucleases, are required for this process, and N6-methyladenosine (m6A) modification on RNA moieties promotes REXO4 localization and R-loop removal in human cells. REXO4 ablation-induced DNA damage stimulates an interferon response and tumor immune infiltration, suppressing mouse squamous cell carcinoma (SCC) progression. Importantly, inhibition of REXO4 potentiates the anti-tumor efficacy of PD-1 blockade against SCC by recruiting and activating CD8+ T cells. Thus, our study provides mechanistic insight into how m6A couples with an exonuclease in R-loop clearance and genome maintenance and uncovers a druggable epitranscriptional machinery that constrains the innate immune response and enables SCC immune evasion.

Metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less responsive to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumour cells and abnormal tumour microenvironment. Here, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumour microenvironment. Hepatocyte-specific phosphatase and tensin homologue (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametrical flow cytometry were performed to analyse the immune landscape alterations. Untargeted metabolomics was conducted to elucidate the hepatic metabolism dysregulation. PCK1 is downregulated in tumour tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumour-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway by directly interacting with the BTB and CNC homology 1 transcription factor, ultimately leading to CD8+ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD-1 treatment increases the antitumour capability of CD8+ T cells and suppresses MASH-HCC development. This study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8+ T cell dysfunction via 12-HETE-p38 signalling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD-1 immunotherapy in MASH-HCC.

Precise manipulation of atomic coordination environments in single-atom nanozymes offers a powerful strategy to regulate catalytic activity, yet achieving simultaneous enhancement of active-site density and intrinsic catalytic efficiency remains challenging. Here, we develop a sulfur-modulated copper single-atom nanozyme (CuN3S) featuring an asymmetric N3S coordination configuration, which differs fundamentally from conventional CuN4 active sites and previously reported S-doped Cu catalysts. The introduction of sulfur not only increases the copper loading density by stabilizing additional atomic Cu centers but also induces distinct electronic redistribution around the Cu active site. Density functional theory calculations reveal that the N3S coordination environment shifts the Cu d-band center toward the Fermi level, strengthens H2O2 adsorption, facilitates interfacial charge transfer, and optimizes Cu-O intermediate formation, thereby promoting superior peroxidase-like catalytic activity. Compared with the CuN4 counterpart, CuN3S exhibits enhanced reactive oxygen species generation under tumor microenvironment conditions, effectively disrupting redox homeostasis and inducing apoptosis, ferroptosis, and immunogenic cell death. In bilateral and metastatic 4T1 tumor models, CuN3S further activates systemic antitumor immunity, resulting in efficient inhibition of both primary and distant tumors. This work establishes coordination-environment engineering of single-atom nanozymes as an effective approach to simultaneously optimize atomic utilization, electronic structure, and catalytic-immune therapeutic outcomes, providing new insights into the rational design of advanced nanozyme-based cancer therapies.

Antibody-drug conjugates (ADCs) and peptide-drug conjugates (PDCs) are modular targeted therapeutics in which molecular recognition is coupled with controlled payload delivery. Owing to their high specificity and precision, they have been regarded as a transformative paradigm for cancer therapy. In this review, current understandings and future perspectives of ADCs and PDCs are synthesized across rational design principles, historical evolution, clinical translation, and emerging formats, aiming to improve practical comprehension and application in oncology. Key determinants of performance: target selection, antibody or peptide carrier attributes, linker stability and cleavage mechanisms, payload classes, and conjugation strategies, are additionally discussed. Milestone advances achieved spanning hematologic malignancies and solid tumors are emphatically summarized to provide a framework by which future conjugate development may be contextualized. In parallel, the expansion of PDCs as complementary platforms is outlined, and advantages are highlighted, while limitations are also considered. ADCs and PDCs still face challenges such as toxicity, resistance, and poor stability. However, through breakthroughs including linker optimization, novel payloads, bispecific designs, and AI-driven approaches, future conjugated drugs will continue to evolve toward personalization, combination therapies, and broader indications. This article provides a systematic synthesis of extant research, thereby facilitating the future advancement of targeted conjugate drugs toward greater precision and individualization. It holds significant academic value as a reference resource and offers practical guidance for the development of novel antineoplastic therapeutics.

Photocatalytic immunotherapy has attracted significant attention due to high selectivity and low side effects. However, the poor tissue penetration of ultraviolet-visible light and the low energy of near-infrared (NIR) photons, combined with the immunosuppressive tumor microenvironment (TME), severely limit catalytic efficiency and immune activation. In this study, we designed a gradient Zn2 +-doping polymeric carbon nitride (PCN) nanocatalyst (gZn-PCN@M), in which the Zn2 + concentration gradually decreases from the interior to the surface of the PCN nanosheets. Under 808 nm laser irradiation, gZn-PCN@M catalyzes the decomposition of H2O in tumor interstitial fluid to produce hydrogen gas, which reduces the intratumoral delivery resistance, markedly enhancing the penetration depth of gZn-PCN into tumors. Meanwhile, the acidic TME and laser irradiation further promote Zn2 + release from gZn-PCN, resulting in abnormally elevated intracellular Zn2 + levels that triggers ROS bursts and disrupts tumor energy metabolism, thereby downregulating PD-L1 expression in tumor cells and activating antitumor immune responses. The results indicated that the inhibition rates of gZn-PCN on primary tumors and distant tumors were 96.51% and 83.69%, respectively. This study proposes a gradient ion-doping strategy for the first time to enhance the NIR responsiveness of photocatalytic nanomedicines, combined with metabolic interference to achieve efficient tumor photocatalytic immunotherapy.

Esophageal squamous cell carcinoma (ESCC) is highly prevalent and aggressive in China, with conventional therapies causing significant morbidity. Photodynamic therapy (PDT) kills tumor cells via photosensitizer-mediated reactive oxygen species (ROS), representing an effective tumor treatment. However, its efficacy is severely impaired by the hypoxic tumor microenvironment (TME). In this study, we synthesized multifunctional carbon dots (SN-CDs) from the traditional Chinese herb Solanum nigrum via hydrothermal method. SN-CDs (particle size: 1.9 ± 0.3 nm) are rich in hydroxyl and amino groups, with an oxygen generation rate of approximately 2.61 ppm/min in vitro. They can efficiently decompose endogenous hydrogen peroxide in the tumor microenvironment, thereby alleviating tumor hypoxia. Under 635 nm laser irradiation, they generate ROS (1O2, ·OH). In vitro, SN-CDs induce apoptosis in ESCC cells (EC9706/EC109) and regulate HIF-1 pathway (downregulate VEGFA, upregulate CDKN1B). In vivo, SN-CD-mediated PDT reduces ESCC xenograft volume by 60% with no obvious systemic toxicity observed in vivo. Thus, SN-CDs are a natural, multifunctional nanoplatform that alleviates tumor hypoxia to enhance PDT efficacy, promising for minimally invasive ESCC treatment.

Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells. The antitumor activity of anti-GITR mAbs depends on the engagement of the fragment crystallizable (Fc) domain to their receptors (FcγRs); however, this has not been comprehensively investigated in human anti-GITR mAbs. Here, we used Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized mice. We identified an Fc-optimized human IgG scaffold that enhances antitumor efficacy through multiple FcγR-mediated mechanisms, including regulatory T cell depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to antitumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human anti-GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.

SUMOylation is characterized as a ubiquitin-like post-translational modification that exhibits mechanistic similarities with ubiquitination. Importantly, it modulates the ubiquitination levels of some target proteins, thereby influencing protein stability. Dysregulation of this modification pathway plays a pivotal role in the pathogenesis and progression of various tumors. While recent studies have demonstrated that protein SUMOylation regulates tumor progression, the specific function and mechanism of Ran-binding protein 2 (RanBP2), an E3 SUMO ligase, remain to be elucidated in lung adenocarcinoma (LUAD). This study demonstrates that RanBP2 exhibits elevated expression in LUAD and correlates with poor prognosis. Functionally, RanBP2 inhibits ferroptosis and enhances the growth of LUAD cells. Mechanistically, RanBP2 augments the SUMOylation of E3 ubiquitin ligase leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1), facilitating its subsequent degradation in the ubiquitin-proteasome pathway, thereby reducing SLC7A11 degradation. The stabilized SLC7A11 protein suppresses ferroptosis and promotes LUAD cell growth. The identified RanBP2 inhibitor, amodiaquine (AQ), in combination with ferroptosis inducer sulfasalazine (SAS), effectively triggered ferroptosis and suppressed LUAD cell growth in vitro and in vivo. This combination enhanced T-cell infiltration and improved anti-PD-1 immunotherapy efficacy. The research identifies a novel RanBP2-LRSAM1-SLC7A11 axis that promotes ferroptosis resistance and LUAD progression. The combination of AQ and SAS represents a promising therapeutic strategy for LUAD.

The low response rate to immunotherapy in patients with lung adenocarcinoma is primarily due to tumor immune evasion. The tumor immunosuppressive microenvironment orchestrates this evasion, yet the underlying mechanisms remain elusive. Here we identify non-specific cytotoxic cell receptor protein 1 (NCCRP1) as a critical and previously uncharacterized regulator of this process. We first analyzed publicly accessible patient-derived single-cell RNA sequencing and RNA sequencing data to investigate the expression of NCCRP1 in lung adenocarcinoma and its impact on the tumor immune microenvironment. Subsequently, the Nccrp1 gene was knocked out in mouse lung adenocarcinoma cells using CRISPR-Cas9. The effect of NCCRP1 deletion on tumor growth was then evaluated using subcutaneous transplantation models in both NSG and C57BL/6 mice. Single-cell RNA sequencing, flow cytometry and multiple targeted in vivo interventions were employed to assess the influence of NCCRP1 on the tumor immune microenvironment. To explore the underlying mechanisms by which NCCRP1 regulates the tumor immune microenvironment, we conducted co-immunoprecipitation, RNA pull-down, ubiquitination assay, mass spectrometry, isobaric tags for relative and absolute quantitation proteomics, dual-luciferase reporter gene assay, and ELISA. Loss of NCCRP1 inhibits lung tumor growth and prolongs survival in immunocompetent C57BL/6 mouse models. NCCRP1 deficiency upregulates CX3CL1 to recruit CX3CR1+ antitumoral macrophages. These macrophages subsequently secrete CXCL9 and CXCL10, enhancing the infiltration of CD8+ T cells and NK cells into the tumor microenvironment. Mechanistically, NCCRP1 and STAU1 competitively bind to NEDD4. NCCRP1 deficiency enhances the STAU1-NEDD4 interaction, promoting ubiquitination and proteasomal degradation of STAU1, thereby increasing CX3CL1 messenger RNA stability. Remarkably, ablating NCCRP1 synergized with anti-programmed cell death protein 1 or interferon-γ therapy, leading to complete tumor eradication. Our findings highlight NCCRP1 targeting as a promising therapeutic strategy to reprogram the immunosuppressive microenvironment and overcome the "cold tumor" phenotype in lung adenocarcinoma.

Messenger RNA (mRNA) therapeutics have emerged as a transformative biomedical platform with broad potential in vaccination, protein replacement, gene editing, and cancer immunotherapy. Despite substantial progress, the broader clinical translation of mRNA therapeutics requires further optimization of delivery systems to address challenges related to stability, biodistribution, intracellular delivery efficiency, and biosafety. In this review, we discuss the rational design of redox-responsive nanomaterials that exploit physiological intracellular redox compartmentalization or, in selected systems, disease-associated oxidative or reductive dysregulation to improve mRNA delivery. We first summarize the biological basis of redox-responsive delivery by linking disease-associated redox imbalance with the engineering principles of responsive nanomaterials. We then systematically discuss major classes of redox-responsive systems, including oxidation-responsive, reduction-responsive, and dual-responsive platforms across polymeric, lipid-based, and hybrid nanomaterial formulations. Particular emphasis is placed on how distinct chemical architectures and responsive motifs influence intracellular delivery behavior, cargo release, immune compatibility, and therapeutic performance. Finally, we discuss current translational challenges, including long-term biosafety, repeated administration, immunogenicity, and large-scale manufacturing, while highlighting emerging opportunities such as AI-assisted material design and personalized theranostic applications. Collectively, this review provides a comprehensive framework for understanding how redox-responsive nanomaterial engineering may advance the next generation of precise and clinically translatable mRNA therapeutics.

Transarterial chemoembolization (TACE) remains a cornerstone therapy for intermediate-to-advanced hepatocellular carcinoma (HCC); however, the optimal embolic platform remains uncertain. This multicenter, retrospective, real-world study (Clinical trial registration number: ChiCTR2500113198) conducted across China compared a novel temperature-sensitive liquid embolic agent, TempSLE-TACE (T-TACE), with conventional drug-eluting bead TACE (D-TACE) in 328 patients with Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Following inverse probability of treatment weighting (IPTW), T-TACE achieved significantly superior objective response rates (ORRs) compared with D-TACE according to both RECIST 1.1 criteria (54.11% vs. 27.78%, P < 0.001) and mRECIST criteria (73.56% vs. 54.93%, P = 0.002). T-TACE was additionally associated with significantly prolonged progression-free survival (median PFS: 12.0 vs. 9.0 months; HR = 0.67, P = 0.001) and overall survival (median OS, 24.0 vs. 15.0 months; HR = 0.49, P < 0.001). Moreover, T-TACE demonstrated a favorable safety profile, with lower incidences of hepatic and gastrointestinal toxicities, including any-grade alanine aminotransferase elevation and hyperbilirubinemia. Subgroup analyses further demonstrated consistent OS, PFS, and ORR benefits across major clinical subgroups, with effect sizes remaining significantly favorable in high-risk populations, including advanced portal vein tumor thrombosis type Vp4, baseline AFP > 1000 ng/mL, and PIVKA-II > 2000 mAU/mL. Exploratory histo-molecular and spatial transcriptomic analyses suggested that T-TACE may promote immune microenvironment remodeling through enhanced Th17-cell infiltration and CD8⁺ T-cell activation, whereas incomplete embolization after D-TACE was more frequently associated with residual intermediate-state tumor cells and an immunosuppressive microenvironment. Collectively, these findings provide preliminary evidence supporting T-TACE as a promising real-world therapeutic strategy for intermediate-to-advanced HCC.

Desmoplastic stroma defines pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. This stroma drives tumor progression, immune evasion, drug resistance, and poor drug delivery. Although targeting tumor stroma has shown preclinical promise, most clinical trials have failed due to limited translational success. A major hurdle is the stroma's extreme heterogeneity and dynamic nature, meaning uniform treatments fail. Emerging evidence supports the existence of distinct 'stromal states' with differential biological functions and therapeutic vulnerabilities. Characterizing these states provides a framework to stratify patients and guide precise, stroma-directed therapies. This review summarizes the clinical landscape of PDAC stroma-targeting strategies, discusses distinct stromal states, and outlines emerging opportunities to exploit the stroma as a therapeutic axis in PDAC to improve clinical trial outcomes.

As renal tumor classification continues to evolve and new hereditary entities emerge, accurate recognition of hereditary renal neoplasms is increasingly important. Advances in precision genomics, genetic testing, and international registries will improve early detection, risk stratification, and precision management.

Background Artificial intelligence (AI)-assisted colonoscopy reduces costs in colorectal cancer screening, but its incremental value relative to non-AI resect-and-discard (RD) strategies for diminutive polyps (≤ 5 mm) remain unclear. We aimed to compare the clinical, economic, and environmental outcomes of AI-assisted and non-AI RD strategies with standard of care (SoC). Methods In our Markov model simulating 6 million individuals aged ≥45 years undergoing screening colonoscopy, 4 strategies were evaluated: SoC, non-AI RD, CADe-assisted RD (CADe-RD), and CADe+CADx-assisted RD (CADe+CADx-RD). The primary outcome was total quality-adjusted life years (QALYs), with secondary outcomes including cost and carbon dioxide (CO₂) emissions. Results Non-AI RD achieved the lowest total cost ($36.6B) and carbon emissions (0.90 million kg CO₂), while yielding the highest QALYs (51.37 million), although differences in QALYs across strategies were small (<0.01%). CADe-RD and CADe+CADx-RD remained cost-saving relative to SoC ($36.9B and $37.4B vs $37.8B, respectively) but were associated with higher costs than non-AI RD. CADe modestly increased adenoma detection without improving QALYs, while the addition of CADx increased costs and emissions and resulted in slightly lower QALYs. Sensitivity analysis showed that CADe+CADx-RD matched or exceeded CADe-RD QALYs only within a limited region of high diagnostic performance. At currently reported CADx performance levels, CADe+CADx-RD yielded lower QALYs and higher costs than CADe-RD. CADe+CADx-RD achieved non-inferiority in QALYs relative to CADe-RD only within a limited region of high diagnostic performance. Conclusions In our non-deterministic model, non-AI RD provided the optimal balance of clinical benefit, cost savings, and lowest environmental impact.

Wilson's disease (WD) is an inherited and treatable disorder of copper metabolism with hepatic or neurological manifestations. It continues to pose challenges in clinical management, and long-term outcome data remain limited. This study investigated hepatic involvement and clinical outcomes in cohorts from Taiwan. Longitudinal data from 146 patients with WD, retrieved from the medical database of a tertiary referral center, were analyzed (mean age at diagnosis 20.7 ± 12.4 years; mean follow-up 16.8 ± 10.8 years; maximum 51.8 years). All patients received standard treatment and care. Nine patients (6.2%) underwent liver transplantation, 6 patients (4.1%) died, and 3 patients (2.1%) developed hepatocellular carcinoma (HCC). Thrombocytopenia <100 K/μL at diagnosis was associated with reduced survival (P=0.0001). Univariate Cox regression identified thrombocytopenia at diagnosis as a strong predictor of liver transplantation or death (P = 0.0001; hazard ratio (HR): 8.41; 95% CI: 2.97-23.78). Consistently, thrombocytopenia <100 K/μL was associated with reduced survival (P < 0.0001) in an external cohort of 155 patients. In the original cohort, the estimated annual HCC risk was 0.12% (95% CI: 0.03-0.36), increasing to 0.86% (95% CI: 0.18-2.5) in those with thrombocytopenia at diagnosis (P=0.029). An exploratory Firth penalized logistic regression showed that older age at diagnosis was associated with higher odds of developing HCC (odds ratio: 1.096; 95% CI: 1.009-1.191; P = 0.031). WD patients have a high rate of liver fibrosis, regardless of whether they present with neurological and hepatic symptoms, and are at risk of developing HCC, warranting lifelong hepatic surveillance.

The global burden of inflammatory bowel diseases (IBD) continues to rise, placing increasing demands on primary care and specialty practices alike. Beyond disease control, patients with IBD face heightened risks related to chronic inflammation and long-term immunosuppressive therapy, including infection, cancer, bone loss, nutritional deficiencies, and mental health disorders. Proactive, structured health care maintenance encompassing vaccination, cancer screening, bone and cardiometabolic health, nutrition, and psychosocial well-being is essential to optimize long-term outcomes. Effective delivery of this care depends on close collaboration and clearly defined shared responsibilities between gastroenterologists and primary care physicians. This review outlines evidence-based strategies for health care maintenance in the outpatient management of adults with IBD.

Perioperative cardiovascular management involves the assessment and identification of risks in patients undergoing surgery, as well as development of a plan for mitigation of those risks during and after the procedure. It includes risk stratification, which provides guidance for preoperative testing and perioperative management in patients at high risk while avoiding overscreening in those at low risk. Specific guidance is informed by the patient's medical comorbid conditions, functional capacity, and type and urgency of planned surgery. In 2024, the American Heart Association, the American College of Cardiology, and other professional organizations published a comprehensive set of evidence-based recommendations for the evaluation and management of cardiovascular risk in adults undergoing noncardiac surgery. Its methodology included systematic literature review, multidisciplinary expert consensus, and peer review. Here, 2 experts in this field, a general internal medicine physician and a cardiologist, debate how to manage the case of an 80-year-old man with multiple cardiopulmonary conditions and other organ system comorbidities who is scheduled to undergo extensive skin cancer surgery. They discuss how to approach preoperative evaluation of such a patient with a focus on optimizing his status and monitoring for cardiac complications during and after the procedure.

The incidence of colorectal cancer (CRC) has risen in recent decades, with a disproportionate increase observed among younger individuals in Japan and other countries. The etiological contribution of the gut microbiota to CRC pathogenesis is recognized, yet the mechanisms involved remain to be fully clarified. Here we integrated whole-genome sequencing (WGS) and transcriptome profiling of CRC with whole-genome metagenomic sequencing of fecal samples to interrogate host-microbiome interactions at high resolution. Application of interpretable artificial intelligence enabled the stratification of CRC into four distinct microbiome-informed subtypes. WGS analysis identified mutational signatures SBS88 and ID18, linked to colibactin exposure, as early clonal events detected in 44.8% of non-hypermutated patients. Notably, these signatures were significantly more frequent among patients born after the 1960s. Microbiome-based subclassification revealed subtype-specific clinical and molecular features. Collectively, our findings indicate that colibactin exposure constitutes a prevalent and potentially modifiable risk factor for CRC in the Japanese population.

In this issue of Cancer Cell, Liu et al. apply spatial multi-omics to map colorectal cancer micrometastases across primary tumors and matched liver and lung metastases, revealing liver micrometastases as an early evolved, stem-like, immune-suppressed residual disease state linked to a six-gene recurrence signature.

Perioperative immunotherapy improves outcomes in locally advanced gastric or gastroesophageal junction cancer (GC/GEJC), but reliable predictive biomarkers remain elusive. In this biomarker-stratified, randomized, multicenter phase 2 Mountain-02 trail (NCT06374901), 136 patients with operable cT3-4aN + M0 GC/GEJC were enrolled and stratified by tumor-specific MHC class II (tsMHC-II) expression status and then randomized (1:1) to receive perioperative tislelizumab plus chemotherapy or chemotherapy alone. Among tsMHC-II-positive patients, adding tislelizumab to chemotherapy significantly increased the major pathological response (mPR) rate compared with chemotherapy alone (61.8% vs. 26.5%, p = 0.003), meeting the pre-specified primary endpoint. In contrast, no significant benefit was observed in the tsMHC-II-negative subgroup. Within the combination therapy arm, tsMHC-II-positive patients also achieved numerically higher mPR (61.8% vs. 23.5%, p = 0.001) and higher pathological complete response (pCR) rate (32.4% vs. 5.9%, p = 0.006) than tsMHC-II-negative patients. These findings support tsMHC-II as a promising predictive biomarker for perioperative immunotherapy and warrant further validation in larger studies.

Traditional bulk-level transcriptomic sequencing cannot link cell type-specific gene expression to patient survival. In this study, we integrate single-nucleus RNA-seq and longitudinal data from 152 patients with pancreatic ductal adenocarcinoma (PDAC), profiling 1.2 million cells to construct a prognostic map connecting cell type-resolved gene expression with overall survival. Using a single-cell-resolved spatial transcriptomic platform, we further analyze 3.1 million cells and correlate their spatial distribution with therapeutic response. To empower the translational research community, we develop ctPANDA, an interactive platform offering cell-type-level prognostic insights. This atlas identifies PLOD2 as a promising target, with elevated expression predicting poorer outcomes across eight cell types. We have developed a proof-of-concept compound that can effectively degrade PLOD2 and inhibit PDAC progression in vivo. Collectively, this study advances the prognostic analysis from bulk-level to cell-type resolution, establishing a framework linking gene expression to clinical outcomes and providing actionable insights for target discovery and precision oncology.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related mortality worldwide. This study was aimed at estimating regional and national variations in lifetime CRC risk worldwide. CRC data were extracted from GLOBOCAN 2022, including 185 countries, and population and all-cause mortality data were sourced from the United Nations. The world was divided into 20 geographical regions and categorized by Human Development Index (HDI). Lifetime CRC risk was estimated with the life table method, adjusted for multiple primary cancers. In 2022, the lifetime risks of developing and dying from CRC were 2.69% [95% confidence interval (CI): 2.68-2.70] and 1.39% (95% CI: 1.39-1.40), respectively. Men had a higher risk of colon cancer than rectal cancer, and higher CRC risk than women. Lifetime risk varied by region and HDI: regions with very high, high, moderate, and low HDI had incidence risks of 5.17%, 2.75%, 0.72%, and 0.57%, respectively, and mortality risks of 2.48%, 1.50%, 0.44%, and 0.41%, respectively. Australia/New Zealand had the highest incidence risk (7.41%, 95% CI: 7.30-7.52), and Northern Europe the highest mortality risk (3.28%, 95% CI: 3.24-3.32). Risks were stable before 40 years of age, peaked in middle age, and declined after 70 years of age. Temporally, Thailand had the highest increasing trend in lifetime risk, whereas the United States and Austria showed a decreasing trend. Lifetime CRC risk differs by subtype, sex, HDI, and geography, and residual risk gradually decreases with age. Targeted primary prevention strategies should be implemented in various countries and regions to mitigate CRC burden.

Lynch syndrome (LS) is a cancer susceptibility syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. Due to increased risk of colorectal cancer (CRC), enhanced colonoscopic surveillance is recommended for heterozygote MMR carriers. Using a registry of English patients with LS linked to digital National Health Service records, we aimed to assess adherence of MMR carriers to national surveillance guidelines and to determine the impact of surveillance on CRC incidence and mortality. We described the frequency of colonoscopies in 4732 MMR carriers and used logistic regression to determine predictors of surveillance adherence. For MMR carriers with a record of surveillance and those without, we estimated age-specific annual CRC incidence rates (AS-AIRs) and cumulative lifetime risks; assessed for stage shift by comparing CRC stage distributions and stage-specific AS-AIRs; and estimated risks of death from CRC and any cause using Kaplan-Meier methods and Cox proportional hazards regression. Surveillance at a mean interval of ≤3 years (n=3028) was associated with a decrease in CRC-specific and all-cause mortality, without an associated change in total CRC incidence, even after multivariate adjustment. No strong evidence of stage shift was observed. Colonoscopic surveillance at a mean interval of ≤2 years (n=1569) was associated with an increase in total CRC incidence. Incidence of early-stage cancers was also higher, with no corresponding decrease in late-stage cancers, which may reflect the short follow-up period, spectrum bias, or the impact of overdiagnosis. The observed reduction in all-cause mortality among regularly surveilled MMR carriers may indicate an impact of surveillance on CRC-specific mortality, though in the context of a non-randomised study could also reflect the influence of selection bias.

Autoimmune gastritis (AIG) has been traditionally recognised as a precursor to type I gastric neuroendocrine tumours and non-cardia gastric adenocarcinoma. However, emerging but scattered evidence suggests that its oncogenic footprint may extend beyond the gastric body to the cardia, gastro-oesophageal junction (GOJ) and oesophagus. In this review, we synthesise the available epidemiological and clinical studies linking AIG and its late manifestation, pernicious anaemia, to cardia/GOJ adenocarcinoma and oesophageal cancers. We discuss putative histopathological, immunological and other mechanisms, including corpus-predominant atrophy, intestinal metaplasia and vitamin B12 deficiency that may create a carcinogenic microenvironment not only in the distal stomach but also at the GOJ and beyond. We highlight diagnostic and epidemiologic challenges that have obscured these associations, including the difficulties in defining the gastric cardia, disentangling autoimmune versus other potential pathways and the under-recognition of AIG in routine practice. Finally, we outline a research agenda aimed at clarifying the malignancy risk across the stomach-cardia-oesophagus continuum, emphasising the need for well-phenotyped cohorts, biomarker-driven risk stratification and refined surveillance strategies. By reframing AIG as a potential hidden gateway to junctional and oesophageal malignancies, we argue that its true oncological significance may be broader than previously appreciated.

The optimal surgical strategy for adenocarcinoma of oesophagogastric junction (AEG) remains debated, particularly regarding lymphadenectomy extent, gastrectomy type and surgical approach, with real-world prospective evidence being scarce. To map lymph node metastasis (LNM) patterns and assess surgical outcomes in a large multicentre cohort of patients with AEG undergoing radical resection. The Chinese League of Adenocarcinoma of Esophagogastric Junction (CLAEG) registry, initiated in 2022 across 44 high-volume Chinese centres, prospectively enrolled AEG patients. This analysis included 2044 radical resections, with LNM assessed by station, stratified by Siewert type and neoadjuvant therapy. Surgical outcomes were compared between total versus proximal gastrectomy and laparoscopic versus open resection. Most tumours were Siewert type II (64.6%) or III (33.4%). LNM was substantially higher in abdominal than mediastinal stations; category-1 nodes (metastasis, >10%) comprised stations 1, 2, 3, 4, 7, 8a, 9 and 11p. The LNM rates for mediastinal stations were 2.77% (No. 110), 0.71% (No. 111) and 0.68% (No. 112). Patients who received neoadjuvant therapy had lower LNM rates, indicating nodal downstaging. Among those undergoing gastrectomy, patients who underwent total gastrectomy had a lower postoperative complication rate than those who underwent proximal gastrectomy (14.8% vs 21.0%; p=0.001) and achieved more extensive lymphadenectomy. Compared with open surgery, patients who underwent laparoscopic resection experienced faster postoperative recovery without higher complication rates (16.5% vs 17.3%). No perioperative mortality occurred. The CLAEG study shows that abdominal lymphadenectomy should be prioritised in AEG, with neoadjuvant therapy, total gastrectomy and laparoscopy associated with favourable short-term outcomes.

This narrative review aims to critically summarize available data on the association between adult acromegaly and metabolic dysfunction-associated steatotic liver disease (MASLD), with a particular focus on clinical associations and treatment implications. From a pathophysiological perspective, growth hormone (GH) may improve hepatic steatosis, inflammation, and fibrosis by acting directly on hepatocytes and indirectly (through insulin-like growth factor-1) on hepatic stellate cells, thereby inducing their senescence. Nonetheless, GH excess may also favor the development of hepatocellular carcinoma, possibly through mechanisms unrelated to hepatic fibrosis. From a clinical perspective, individuals with acromegaly have low rates of hepatic steatosis and visceral adipose tissue (VAT), but high insulin resistance (IR), which contradicts the generally observed positive association between IR and VAT or hepatic steatosis. By contrast, limited data do not support lower rates of hepatic fibrosis in acromegaly, possibly because GH excess is controlled after diagnosis. From a therapeutic perspective, published evidence, derived mainly from case series, suggests that surgical or pharmacological management of acromegaly increases hepatic steatosis and VAT, despite decreasing IR. However, the long-term effect of acromegaly control on hepatic inflammation and fibrosis remains largely unknown. Acromegaly is associated with IR, type 2 diabetes mellitus, hypertension and cardiovascular disease; however, acromegaly is inversely associated with VAT and MASLD. Further mechanistic and clinical studies are warranted to better elucidate the intriguing association between acromegaly and MASLD.

Cancer type classification is challenging due to tumor heterogeneity and undefined tissue of origin (TOO), particularly in cancers of unknown primary (CUP) and multiple primary cancers (MPC). Accurate TOO identification is critical for guiding treatment and prognosis. We developed a stacked ensemble machine learning classifier that integrates 11 multidimensional cfDNA features spanning genomic, fragmentomic, methylation/repeat, and microbial signals. Base models were constructed using five algorithms, including Deep Learning, Distributed Random Forest, Gradient Boosting Machine, Generalized Linear Model, and XGBoost, within a five-fold cross-validation framework, and their predictions were aggregated into a final ensemble optimized for top-1 accuracy. The classifier achieved robust performance across 17 cancer types, with top-1 and top-2 accuracies of 78% and 89% in the training cohort (n = 1,814), and 80% and 90% in an independent validation cohort (n = 1,221). Notably, predictive performance was retained in samples with low tumor fraction (71% top-1, 85% top-2). Sensitivity varied across tumor types, with the highest performance observed in head and neck and colorectal cancers. Among CUP cases, 11 of 15 (73.3%) predictions matched clinically inferred primary sites based on multimodal diagnostics. Feature importance analysis identified nucleosome positioning, fragment size distribution, and repeat elements as key contributors to model performance. Collectively, this cfDNA-based classifier provides a robust and non-invasive approach for accurate cancer type identification and has the potential to support clinical decision-making.

Hepatocellular carcinoma (HCC) exhibits substantial molecular and morphological heterogeneity. The recently updated 6th edition of the World Health Organization Classification of Digestive Tumours recognizes nine specific HCC subtypes, each characterized by distinct morphomolecular and clinical profiles. Although these subtypes account for approximately 35% of all HCC cases, the remaining 65% are classified as conventional HCCs. These subtypes are categorized based on their prognostic implications: the unfavorable prognosis group comprises macrotrabecular-massive, sarcomatoid, and neutrophil-rich HCCs; the comparable prognosis group includes steatohepatitic, fibrolamellar, and chromophobe HCCs; and the favorable prognosis group consists of lymphocyte-rich and clear cell HCCs. By contrast, scirrhous HCC is associated with various clinical outcomes. Furthermore, this classification includes two newly recognized patterns: vessels encapsulating tumor clusters and CTNNB1-mutated HCC. The imaging features of HCC are significantly correlated with its molecular-pathological characteristics. In particular, aggressive subtypes frequently present with specific imaging hallmarks such as rim arterial phase hyperenhancement, diffuse arterial phase hypo-enhancement, and intratumoral necrosis on T2-weighted imaging, which serve as critical noninvasive predictors of clinical outcomes. However, a definitive diagnosis of specific subtypes based solely on imaging remains challenging. This review provides a comprehensive overview of the molecular, pathological, and radiological characteristics of HCC subtypes and patterns, emphasizing that a detailed understanding of these features is essential for informed therapeutic decision-making and accurate prognostic assessment.

Liver fibrosis, a pathological process characterized by excessive production of extracellular matrix (ECM) and sustained activation of hepatic stellate cells (HSCs), can further progress into cirrhosis and hepatocellular carcinoma. The disorder has imposed a heavy burden on global public health, resulting in millions of deaths annually. Mitophagy maintains mitochondrial function by eliminating dysfunctional mitochondria and regulating the biogenesis of new ones. It has been reported that mitophagy participates in the progression of liver diseases. However, the exact function of mitophagy in liver fibrosis remains unclear. In this review, we first outline the current knowledge regarding mitophagy regulatory mechanism. We then focus on the effect of mitophagy in the progression of liver fibrosis by regulating HSCs activation, oxidative stress, inflammatory signaling cascades, lipid metabolism reprogramming, and the modulation of the immune microenvironment. We further highlight that mitophagy mainly plays a protective role against liver fibrosis, whereas excessive mitophagy may exacerbate liver fibrosis by clearing healthy mitochondria aberrantly. Moreover, we summarize clinical data supporting mitophagy-targeted therapeutic strategies for liver fibrosis. Elucidation of these issues will offer new perspectives on the function of mitophagy during liver fibrosis, as well as potential strategies for anti-fibrotic therapy.

Cancer immunotherapy is often hindered by the immunosuppressive tumor microenvironment and the inefficient activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway under hypoxic conditions. To address these challenges, we developed a hierarchical core-shell Au@Co-EGCG/Mn-EGCG (ACM) nanoplatform that synergistically integrates radiosensitization with a dual-track STING amplification strategy. Owing to its high-Z gold core and robust catalase-like activity, the ACM nanostructure effectively alleviates tumor hypoxia and maximizes X-ray energy deposition, leading to an intense burst of reactive oxygen species (ROS) and irreparable DNA damage. This synergy in turn triggers potent immunogenic cell death and substantial mitochondrial DNA (mtDNA) leakage. Critically, the hierarchical release of Mn2+ and Co2+ ions within tumor cells establishes a "sequential synergistic cascade": Mn2+ sensitizes cGAS for enhanced DNA recognition, while Co2+ acts as a high-gain amplifier by enhancing the binding affinity of STING for 2', 3'-cyclic GMP-AMP (cGAMP). This molecular relay ignites a systemic surge of pro-inflammatory cytokines, notably IFN-β, effectively converting "cold" tumors into "hot" ones. In vivo, ACM-mediated radiotherapy not only achieves thorough in situ tumor ablation but also elicits a powerful abscopal effect, suppressing distant metastasis through enhanced T-cell infiltration and macrophage repolarization. Collectively, this work establishes a potent radio-metalloimmunotherapy paradigm to overcome radioresistance and systemic cancer progression. STATEMENT OF SIGNIFICANCE: The majority of colorectal cancers are microsatellite stable (MSS) and resistant to immunotherapy due to a "cold" tumor microenvironment. In this study, we introduce a hierarchical core-shell nanoparticle that, upon X-ray irradiation, sequentially releases two metal ions to activate the cGAS-STING pathway cooperatively. Unlike conventional single-agent STING agonists, our design separates the DNA sensitization provided by Mn2+ from the signal amplification driven by Co2+, creating a synergistic cascade that overcomes hypoxia-induced immunosuppression. This dual-track mechanism transforms resistant MSS tumors into immune-responsive "hot" lesions, eliminating primary tumors and suppressing distant metastases. The work establishes a new paradigm of radio-metalloimmunotherapy, offering a translatable strategy to convert radiation into a systemic immune adjuvant.

Colorectal cancer (CRC) metastases frequently recur due to minimal residual disease (MRD) and persistent micrometastases after therapy. Here, we performed spatial multimodal profiling using spot-level and high-resolution spatial transcriptomics, multi-regional whole-genome sequencing following laser-capture microdissection, and high-plex protein imaging to map 49 tumors from 19 patients, encompassing paired primary CRC and matched liver (CLiM) and lung (CLuM) metastases. Phylogenetic reconstruction revealed that liver micrometastases (CLiMi) arose from early clonal divergences and harbored a stem-like, quiescent state consistent with metastatic dormancy. Spatially, we uncovered distinct stromal barriers: macrometastases were encapsulated by myofibroblasts, whereas micrometastases were surrounded by immunosuppressive niches characterized by T cell exhaustion and distinct ligand-receptor signaling networks. Notably, we identified a CLiMi-specific six-gene signature associated with MRD status, disease-free survival, and chemotherapy resistance across multiple independent cohorts. These findings elucidate the spatial evolutionary landscape of CRC metastases and provide tissue-based spatially validated biomarkers for surveillance and therapeutic targeting.

Phosphatidylethanolamine binding protein 4 (PEBP4) is a multifunctional protein. The role of intracellular PEBP4 in cancer is well established. However, as a secreted protein, its extracellular functions have yet to be elucidated. Thus, the present study attempted to decipher the functions of the secreted PEBP4. Here, we demonstrated that PEBP4 was upregulated in colorectal cancer (CRC) specimens and was also elevated in the serum of CRC patients. Our results revealed that the secreted PEBP4 (sPEBP4) stimulated the proliferation and migration of colon cancer cells, an event that was prevented by treatment with antibodies against PEBP4 or by mutating the N-glycosylation site (N169 to Q). Our studies indicated that the action of sPEBP4 was different from that of its cellular counterpart. Further, co-injection of the sPEBP4 with colon cancer cells promoted tumorigenesis and lung metastasis in vivo. Mechanistically, sPEBP4 increased phosphorylation of Smad2/3 and Akt/mTOR, which was blocked by the TGFβRⅠ inhibitor SB525334, siRNA or a dominant-negative mutant of TGFβRI, but not by knockdown of IGF-1R or EGFR. In vitro surface plasmon resonance assay revealed that sPEBP4 directly associated with TGFβRs. Finally, sPEBP4 enhanced the stability of TGFβRI by upregulating USP4 through a mechanism similar to TGF-β. Collectively, our study for the first time demonstrates that sPEBP4 activates the TGF-β signaling pathway to promote CRC progression in a TGFβ-independent manner. This would prompt further studies to explore if sPEBP4 could serve as a potential candidate for colorectal cancer therapy or a biomarker for diagnosis, prognosis, and therapeutic responses.

Cholangiocarcinoma is a highly malignant tumor with an increasing incidence around the world. Discovery of novel molecular targets and effective therapies for cholangiocarcinoma are urgently needed. Palmitoylation is a reversible lipid modification mainly catalyzed by ZDHHC family palmitoyltransferases. However, its function and underlying mechanisms in cholangiocarcinoma remain poorly understood. Here, we found that protein palmitoylation levels and ZDHHC5 expression were upregulated in cholangiocarcinoma. Knockdown of ZDHHC5 inhibited the growth of cholangiocarcinoma. Mechanistically, ZDHHC5 modulates the activity of MAPK signaling pathway by regulating palmitoylation of BRAF at Cys194/195. Palmitoylation facilitates the membrane localization of BRAF and stabilizes BRAF protein. Either knockdown of ZDHHC5 or disruption of palmitoylation sites of BRAF inhibited ERK signaling. Furthermore, we found that cholangiocarcinoma cells expressing high levels of ZDHHC5 exhibited increased activities of MAPK signaling pathway and increased sensitivities to MAPK signaling pathway inhibitors. This study identifies a previously unknown ZDHHC5-BRAF-ERK axis that promotes the growth of cholangiocarcinoma and represents a potential crucial role in therapeutic.

Cancer-associated fibroblasts (CAFs) are central players in the tumour microenvironment (TME) of primary liver cancer, influencing both cancer progression and treatment response. Studies involving single-cell RNA sequencing and spatial multi-omics have significantly expanded our understanding of CAF heterogeneity and functional diversity, although consolidated markers to identify CAF subtypes and therapy-dependent plasticity remain largely unknown. In this review, CAF subpopulations, including their markers and functions, are comprehensively summarised in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The spatial distribution of CAF subtypes from tumour core to boundary correlates with their phenotypes and functions. We focus on mapping dynamic changes of CAF subtypes in response to therapy, including chemotherapy and immunotherapy, and how these changes influence treatment response and prognosis in liver cancer. Finally, we discuss key challenges in targeting specific CAF subtypes and general CAF activation pathways in current clinical trials. This review provides a holistic view of the current and future landscape of CAF-targeting and CAF-regulating strategies in combination with standard-of-care treatments for liver cancer.

This study modeled and optimized ultrasound-assisted extraction (UAE) of phenolic compounds from 'Granny Smith' apple peel (RM) and biofortified peel subjected to controlled abiotic stresses (RM-E). A Box-Behnken design evaluated the effects of extraction ratio, ethanol concentration, and ultrasound power on total phenolic compounds (TPC), while extraction kinetics were described using the Peleg model. Optimal conditions were 1:36 w/v, 76% ethanol, and 52% ultrasound power, yielding extracts with 20-23 g kg-1 TPC and a profile dominated by flavonols and flavan-3-ols. After simulated gastrointestinal digestion, the biofortified UAE extract (USRM-E) showed 39.8% TPC bioaccessibility. Its intestinal fraction exhibited antiproliferative effects against HT-29 and Caco-2 colorectal cancer cells and showed antioxidant, anti-inflammatory, and anti-adipogenic responses in vitro. Overall, combining abiotic stress-induced biofortification with UAE improved phenolic recovery and bioaccessibility, supporting apple peel by-products as sustainable sources of bioactive ingredients for functional food applications through green extraction technologies and valorization strategies.

Inhibiting tumor angiogenesis is a recognized anticancer strategy. VEGFR2 is a key driver of pathological angiogenesis via VEGF signaling. Natural chalcones can target VEGFR2 but are limited by weak activity and low yield. To design and synthesize novel chalcones as VEGFR2 inhibitors to suppress tumor angiogenesis, thereby offering a new anti-angiogenic strategy for colorectal cancer (CRC). A series of novel chalcones was synthesized, and compound 27j, bearing a bis-Michael acceptor moiety, was selected. Its binding affinity to VEGFR2 was assessed by surface plasmon resonance (SPR), and a kinase selectivity profile was generated. The effects on VEGFR2 activation and downstream signaling pathways were analyzed. Anti-angiogenic effects and inhibition of CRC growth were evaluated through in vitro experiments, in vivo animal studies, and patient-derived xenograft (PDX) models. Pharmacokinetics, ADME, and acute/chronic toxicity were characterized. Compound 27j demonstrated some binding affinity for VEGFR2 in SPR assays. However, it did not exhibit significant inhibitory activity in enzymatic kinase assays, suggesting that its mechanism of action may differ from classical ATP competition. In vitro and in vivo studies confirmed that 27j effectively inhibits key angiogenetic processes and interferes with VEGFR2 activation and its downstream signaling. In PDX models, angiogenesis was inhibited in tumors from the 27j-treated group, and there was a trend toward delayed CRC growth. Compound 27j represents a novel VEGFR2 inhibitor whose mechanism may involve non-classical rather than direct ATP competition. It exhibits promising anti-angiogenic and anti-tumor activity in CRC models, supporting its further investigation as a promising lead compound for anti-tumor angiogenesis therapy.

Liver fibrosis is a progressive pathological process driven by liver injury, including viral hepatitis and metabolic dysfunction-associated steatohepatitis (MASH), and can progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Hepatocyte-hepatic stellate cell (HSC) crosstalk plays a central role in disease progression, but its regulatory mechanisms remain incompletely understood. This study aimed to define hepatocyte-HSC crosstalk in liver fibrosis mediated by microRNA-149-5p (miR-149-5p) signaling and to explore its potential as a therapeutic target for intervention. Differentially expressed exosomal microRNAs were identified by RNA sequencing of hepatocyte-derived exosomes from fibrotic and control livers. Functional screening using collagen type I alpha 1 chain (COL1A1) reporter assays identified miR-149-5p as an anti-fibrotic candidate. Exosome-mediated intercellular communication was confirmed using co-culture systems and confirmed by tumor susceptibility 101 (TSG101) silencing. Liver fibrosis was induced by bile duct ligation (BDL) and thioacetamide (TAA) in mice. Therapeutic effects were evaluated using AAV-mediated hepatocyte-specific overexpression and miR-149-5p agomir administration. miR-149-5p was selectively enriched in hepatocyte-derived exosomes via a CCUC-based EXOmotif and directly targeted PDGFRB in HSCs, thereby inhibiting HSC activation, proliferation, and collagen deposition without affecting hepatocyte function. During fibrosis progression, PU.1 bound to the miR-149-5p promoter and suppressed its transcription, leading to reduced exosomal miR-149-5p delivery and consequent PDGFRB derepression in HSCs. Both AAV-mediated overexpression and systemic miR-149-5p agomir administration significantly attenuated BDL- and TAA-induced liver fibrosis, as evidenced by reduced collagen deposition, decreased hydroxyproline content, and downregulation of HSC activation markers. The PU.1 (hepatocyte)-miR-149-5p (exosome)-PDGFRB (HSC) axis represents a key regulatory pathway in liver fibrosis, wherein PU.1 represses miR-149-5p transcription in hepatocytes, leading to EXOmotif-dependent reduction of exosomal miR-149-5p delivery and consequent derepression of PDGFRB in HSCs, thereby promoting HSC activation and fibrosis progression. Importantly, miR-149-5p agomir administration offers a promising therapeutic strategy for liver fibrosis.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.

The generation of highly plastic cell states in colorectal cancer that are prone to metastatic dissemination involves complex epigenetic reprogramming, rather than new genetic traits. Goto et al.1 implement a serial orthotopic organoid transplantation framework to uncover the idea that losing Gata6, a guardian of the colonic lineage, promotes metastatic competence.

The recognition of mislocalized DNA and RNA by cGAS-STING, RIG-I/MDA5, the OAS-RNase L axis, and endosomal TLR3/7/8 has emerged as a unifying paradigm linking cancer, autoinflammation, and antiviral immunity. Counterbalancing these sensors is a structurally heterogeneous nuclease repertoire whose distinct substrate specificities, subcellular compartments and pH optima constrain ligand availability in space and time. Disruption of this equilibrium drives disease through two mirror-image mechanisms. In cancer, DNASE1 is inactivated by tumor-derived G-actin, DNASE1L3 is transcriptionally silenced in hepatocellular, colorectal and lung adenocarcinomas, and DNASE2 is upregulated in immunologically "cold" tumors, together permitting neutrophil-extracellular-trap-mediated exclusion of cytotoxic T cells and suppression of cytosolic DNA sensing. In autoimmunity, biallelic loss of DNASE1L3, TREX1, RNase H2, ADAR1 or RNase T2 produces the interferonopathies of systemic lupus and Aicardi-Goutières syndrome. Diagnostically, nuclease-specific cleavage signatures have matured into cell-free DNA fragmentomics validated across 13 cancer types in a 3,021-patient cohort; therapeutically, the field now spans engineered actin-resistant DNASE1/DNASE1L3 biologics, selective TREX1 and ADAR1 inhibitors entering first-in-human evaluation, STING-activating nanomedicines, RNase Fc-fusions such as RSLV-132 in phase 2a lupus, and JAK1/2 inhibition as standard of care in Aicardi-Goutières syndrome. We synthesize this evidence as a two-fate problem: whether an endogenous nucleic acid accumulates at these sensors to drive autoinflammation or is cleared by nucleases before detection is set by the balance between sensor engagement and clearance capacity. The therapeutic corollary acts on the ligand rather than the enzyme, restoring ligand availability where disease is malignant and restoring clearance where disease is self-directed.

Primary sclerosing cholangitis-associated UC (PSC-UC) carries excess colorectal neoplasia despite often mild-appearing endoscopy, implicating persistent microscopic inflammation and microbiota-bile acid (BA) dysfunction. To test whether PSC-UC neoplasia is driven by transferable microbiota-mediated inflammation linked to secondary BA loss. Surveillance colonoscopies (2012-2022) from PSC-UC (n=251) and UC-only (n=8839) were compared for segmental endoscopic/histological activity and dysplasia. We generated multidrug resistance protein 2 (MDR2)-/- × interleukin (IL)-10-/- double-knockout (DKO) mice and used germ-free (GF) derivation, faecal microbiota transplantation (FMT), antibiotic conditioning and cohousing with shotgun metagenomics and liquid chromatography-tandem mass spectrometry BA profiling. PSC-UC showed greater inflammatory activity and a right-shifted dysplasia burden versus UC-only. Under specific-pathogen-free conditions, DKO mice developed early right-predominant colitis and multifocal dysplasia progressing with age. DKO communities were depleted of 7α-dehydroxylation capacity with near absence of deoxycholic and lithocholic acids and no enrichment of canonical bacterial genotoxins. GF DKO mice were protected, whereas live DKO donor FMT reinstated severe colitis and dysplasia; sterile-filtered stool supernatant was inactive. IL-10-/- donor FMT or cohousing attenuated colitis and increased recipient secondary BA, whereas wild-type/MDR2-/- donor transfers were non-colitogenic. In GF DKO mice, direct deoxycholic acid repletion caused hepatotoxicity. PSC-UC neoplasia associates with transmissible microbiota-dependent inflammation and secondary BA deficiency. Controlled restoration of BA-transforming microbial functions, rather than indiscriminate secondary BA replacement, is a rational translational direction.

RNA 5-methylcytosine (m5C) has emerged as a critical epigenetic regulator in cancer biology, yet its role in the tumour immune microenvironment (TME) remains incompletely understood. We aimed to elucidate the functional role and underlying mechanism of NOP2/Sun RNA methyltransferase 6 (NSUN6), an m5C methyltransferase, in shaping the TME of pancreatic ductal adenocarcinoma (PDAC). The clinical significance of NSUN6 was assessed in human PDAC cohorts. The impact of NSUN6 on antitumour immunity was evaluated using murine PDAC models. Single-cell RNA sequencing was employed to characterise the TME landscape of PDAC. RNA bisulfite sequencing and RNA sequencing were used to identify NSUN6 targets. The synergistic effects of C-C motif chemokine ligand 2 (CCL2) blockade combined with immune checkpoint blockade (ICB) therapy were investigated. NSUN6 deficiency significantly enhanced macrophage accumulation and polarisation toward immunosuppressive phenotypes, thereby impairing CD8+ T cell-mediated antitumour immunity in PDAC. Mechanistically, NSUN6 deficiency downregulated KDM5A expression in an m5C-dependent manner, resulting in transcriptional activation of CCL2. Elevated CCL2 secretion promoted the accumulation and polarisation of protumorous macrophages, fostering an immunosuppressive TME and inducing resistance to ICB. Notably, CCL2 blockade reversed protumorous macrophage infiltration and restored ICB sensitivity in Nsun6-deficient murine PDAC models. Clinical analysis further revealed a positive correlation between NSUN6 expression and favourable immune responses in ICB-treated cohorts. NSUN6 deficiency drives immune suppression through the m5C-KDM5A-CCL2 axis in PDAC. Targeting the NSUN6-CCL2 axis represents a promising strategy to sensitise PDAC to ICB therapy.

Metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma (MASLD-HCC) is an emerging malignancy with limited therapeutic options. The identity and function of cancer stem cells (CSCs) in MASLD-HCC remain poorly understood. In this study, we characterised CSCs in MASLD-HCC and investigated their contribution to MASLD-HCC tumourigenesis and therapy response. We performed expression profiling in human MASLD-HCC samples (n=29 pairs of tumour and adjacent normal tissues). Advanced in vivo genetic lineage tracing coupled with single-cell RNA sequencing was used to characterise CD133+ CSCs in preclinical models. To establish causality, we developed a hepatocyte-specific CD133-overexpressing mouse model of MASLD-HCC. We identified CD133 protein interactors by mass spectrometry. A novel strategy combining CD133-targeted small interfering RNA (siRNA) nanoparticles with first-line therapy was assessed in clinically relevant MASLD-HCC models. CD133+ CSCs were significantly enriched in human MASLD-HCC tumours and positively correlated with established markers of malignancy. In vivo genetic lineage tracing in mice revealed that CD133+ cells exhibit hallmark CSC properties, including self-renewal, tumour-initiating capacity and multipotent differentiation, as compared with CD133- counterparts. Hepatocyte-specific CD133 overexpression in mice accelerated MASLD-HCC tumourigenesis. Mechanistically, CD133 interacts with myosin heavy chain 9 (MYH9) to stabilise active β-catenin, thereby propagating Wnt/β-catenin signalling that drives CSC phenotypes and tumourigenic potential. Therapeutically, genetic ablation of CD133+ cells or systemic delivery of CD133-siRNA nanoparticles potently sensitised MASLD-HCC to sorafenib and lenvatinib, significantly improving outcomes in MASLD-HCC. This study established CD133+ CSCs as critical mediators through the CD133-MYH9/β-catenin axis in MASLD-HCC. Targeting CD133 enhances multikinase inhibitor efficacy, offering a promising therapeutic strategy for MASLD-HCC.

Metal alkoxides hold promise in catalysis and materials science, but their rapid hydrolysis in aqueous media represents a major limitation for biomedical applications. To harness this intrinsic reactivity therapeutically, we developed a facile ultrasonication-assisted dispersion method to fabricate nanoscale copper ethoxide (CuOEt) with subsequent screening showing their ready dispersion in Lipiodol to form a stable injectable suspension (CuOEt@LPD). Unlike bare CuOEt nanoparticles, which suffered from rapid degradation, a burst release of ethanol, and conversion to copper oxide in water, the CuOEt@LPD formulation utilized a Lipiodol protection strategy to create an effective barrier against water, enabling a sustained release of ethanol. Functionally, the released ethanol upregulated intracellular cytochrome P450 2E1 (CYP2E1), triggering metabolic oxidative stress in hepatocellular carcinoma cells, which acted synergistically with released copper ion-induced cuproptosis, ultimately leading to robust cell death. Furthermore, the Lipiodol dispersant served as a potent radiosensitizer, significantly enhancing the tumor-inhibiting efficacy upon radiotherapy in an H22 murine hepatoma model. Notably, we discovered that this trimodal therapeutic strategy could also initiate a robust antitumor immune response, which established long-lasting immunological memory, thereby effectively suppressing tumor recurrence and metastasis. Our work successfully establishes metal alkoxides nanoparticles as a highly promising class of nanotherapeutic agents for hepatocellular carcinoma treatment.

Oxidative-stress-related diseases generate elevated levels of hydrogen peroxide (H2O2) and other redox-active species in exhaled breath condensate (EBC), offering a promising avenue for non-invasive disease assessment. Despite its diagnostic potential, clinical translation of EBC redox species detection has been constrained by bulky analyzers, labor-intensive operation, and limited sensitivity. By harnessing the redox potential, we present a Redox-mediated Optochemical Plasmonic Sensing (ROPS) system, an ultrasensitive platform that enables real-time, easy-to-use, point-of-care quantitative analysis of H2O2-equivalent reducing capacity in EBC. By coupling H2O2-triggered gold nanoparticle growth on a phase-modulated plasmonic sensor, the ROPS system based on the phase-modulated interferometry achieved a detection limit of 1.19 pM and a wide dynamic range across 4 orders of magnitude. Moreover, the ROPS system demonstrated excellent reusability, maintaining stable H2O2 sensing performance over 40 reuse cycles. To enable point-of-care applications, we further developed a handheld high-efficiency EBC sampler, which harvested exhaled condensate at 2.49 μL/s and enabled an EBC-ROPS sampling-to-biosensing workflow down to 15 min. Clinical evaluation using EBC samples from lung and esophageal cancer patients and matched controls confirmed reliable quantification of trace H2O2-equivalent Au(III)-reducing capacity in complex EBC matrices, highlighting the potential of the integrated ROPS platform as a practical tool for point-of-care and non-invasive oxidative stress-related disease assessment.

Liquid biopsy of pancreatic cancer via circulating tumor DNA (ctDNA) is challenged by the extreme rarity of targets, a limitation that conventional passive biosensors cannot overcome. Here, we engineered an intelligent micromotor that actively captured, transported, and electrochemically reported ctDNA. The asymmetric flask-shaped micromotor (HPCMF) was constructed from carbonaceous micro-flasks (CMF) decorated with platinum nanoparticles (PtNPs) and supramolecular (HP5) stabilized PtNPs. The HP5 moieties served as docking sites for methylene blue-labeled assist-DNA (MB-aDNA) via host-guest interactions, creating a mobile capture interface. Propelled by PtNP-catalyzed bubble generation from H2O2, the micromotor reached an average speed of 56.16 μm s-1 (5% H2O2). Upon recognizing target DNA (tDNA) in serum, it autonomously navigated to a probe DNA-modified (pDNA) glassy carbon electrode, where a ternary complex (MB-aDNA/tDNA/pDNA) assembled and anchored, positioning MB for efficient electron transfer. This active enrichment strategy achieved a linear range of 1 pM - 10 μM, a detection limit of 0.18 pM, accurate quantification in simulated pancreatic juice and mouse serum (recoveries 76.5-106.2%), and a 52.4% reduction in assay time relative to digital PCR (dPCR). This work establishes a generic "mobile sensing" framework for next-generation autonomous diagnostic devices.

Cancer poses a significant burden on human health and has emerged as a pressing global public health issue. Conventional cancer therapies are constrained by poor spatial precision in drug delivery, inadequate immunogenic cell death, and persistence of immunosuppressive M2-like tumor-associated macrophages. These limitations perpetuate off-target toxicity, immune evasion, and tumor recurrence. In this study, we engineered an integrated therapeutic platform, HA/IR780@Bac, through leveraging hypoxia-responsive Escherichia coli to co-deliver immunomodulating hyaluronic acid (HA) and the photothermal agent IR780 for synergistic cancer eradication. The system exploited bacterial tropism to achieve tumor-targeted accumulation, and mediated localized photothermal ablation of tumor cells while concurrently triggered robust immunogenic cell death. This immunogenic cell death cascade-initiated cancer immunogenicity and reversed immunosuppression, which was further amplified by HA-driven polarization of tumor-associated macrophages from pro-tumoral M2 to antitumoral M1 phenotype. Therefore, the HA/IR780@Bac system, which combined targeted delivery, photothermal effect, immunogenic cell death activation, and macrophage reprogramming, could establish a robust paradigm for synergistic tumor treatment.

The mechanisms by which tumor-derived extracellular vesicles and particles (EVPs) promote vascular permeability during premetastatic niche formation remain unclear. Here, we show that tumor EVPs rapidly induce vascular leakiness within 1 h of administration in female mice, creating a permissive environment that enhances metastatic seeding. Rather than acting directly on endothelial cells, EVPs activate NF-κB and JAK-STAT signaling in interstitial macrophages, leading to IL-6 secretion and increased vascular permeability. Interstitial macrophage depletion markedly reduces EVP-induced vascular leakiness and metastasis. We identify extracellular vesicle-associated integrin α5 (ITGα5) as a major functional determinant of this process, promoting macrophage activation and IL-6 secretion without affecting EVP uptake. EVPs derived from colorectal cancer tumors with high ITGα5 similarly induce macrophage IL-6 secretion and vascular permeability. Together, these findings define an EVP-macrophage-IL-6 axis that drives vascular permeability during premetastatic niche formation and identify EVP-associated ITGα5 as a key mediator of metastatic progression and a potential therapeutic target.

Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.

Phenotypic plasticity is a hallmark of cancer1; however the molecular switches required for cell-fate reprogramming are poorly understood. During intestinal wound-healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth2-10. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC11-15, is a pivotal stress-responsive orchestrator of dynamic dedifferentiation. In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, ZFP36L2 binds to stress-associated mRNAs that contain AU-rich 3' untranslated regions, which induces the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response. Together, these data show that ZFP36L2 acts as an important molecular switch that couples stress sensing with phenotypic plasticity. This in turn drives cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2-deficient CRC, the inability to re-enter the LGR5+ state during metastatic outgrowth promotes non-canonical lineage plasticity, which is associated with poor clinical outcomes.

Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines1. Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models. Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR-Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR-RAS-MAPK axis uncovered differential effects of KRAS variant alleles. This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology.

Targeting RNA-binding proteins has been shown to be challenging due to the absence of druggable pockets. Recently, Lu et al. identified a molecular glue capable of degrading HuR and suppressing BRAF-mutant colorectal cancer. These findings offer a promising therapeutic pathway for the treatment of a subset of HuR-driven malignancies.

Histone lactylation is an epigenetic modification triggered by lactate produced during glycolysis. In cancer, histone lactylation can coordinate metabolic and epigenetic states to promote tumor development and progression. Here, we identified circ2891 as a driver of metabolic reprogramming and histone lactylation in colorectal cancer (CRC). In patients, circ2891 was aberrantly upregulated in tumors and correlated with poor outcomes. Elevated circ2891 potentiated aerobic glycolysis and lactate production in CRC cells, supporting enhanced cell proliferation and tumor growth. Mechanistically, circ2891 specifically interacted with the m6A reader FXR1 and facilitated its phase separation, which stabilized PGK1 and ENO1 mRNAs by enhancing the recognition of their m6A modification sites. Consequently, elevated PGK1 and ENO1 led to increased aerobic glycolysis and drove histone lactylation, thereby transcriptionally activating the RNA helicase DDX21 to promote CRC progression. Simultaneously targeting circ2891 and histone lactylation suppressed patient-derived organoid and xenograft tumor growth. Together, these findings show that circ2891 promotes CRC by stabilizing PGK1/ENO1 via phase separation of FXR1, boosting glycolysis and histone lactylation to activate expression of DDX21. Targeting circ2891 offers a promising therapeutic strategy enhancing clinical outcomes.

Cancer-associated fibroblasts (CAFs) drive key aspects of tumor malignancy. However, the profound heterogeneity in cytokine secretion and cell-cell communication orchestrated by CAFs renders therapeutic strategies targeting these molecules largely ineffective against cancer. In contrast, exploring the metabolic reprogramming mechanisms of CAFs could be conducive to therapeutic intervention in colorectal cancer (CRC). Here, we conducted metabolomic and single-cell RNA-sequencing analyses that uncovered increased glycolysis, intracellular lactate, and histone lactylation in CAFs compared to normal fibroblasts (NFs). Elevated histone 3 lysine 18 lactylation (H3K18la) in CAFs promoted the transition of CAFs to myofibroblastic CAFs (myCAFs), increased collagen deposition, and enhanced organoid growth. Furthermore, fibroblast-specific conditional lactic dehydrogenase A (Ldha) knockout in a mouse model mitigated CRC tumorigenesis and progression in vivo. Cancer cell-derived TGF-β accelerated metabolic reprogramming and histone lactylation in CAFs. NPM1, a histone chaperone functioning as a cofactor of P300, enhanced the H3K18la level of the ROCK1 promoter and activated ROCK1 transcription. The RhoA/ROCK1/MLC2/MRTF-A pathway and extracellular matrix (ECM) remodeling were indispensable for the tumor-promoting effect of CAF histone lactylation in CRC. Furthermore, CAF histone lactylation limited CD8+ T cell infiltration and aggravated CD8+ T cell exhaustion via ECM remodeling. Stiripentol, a clinical drug that targets lactylation, potentiated the efficacy of immunotherapy in CRC models. Together, this study demonstrates that elevated lactate levels in CAFs reprogram the epigenetic landscape to promote tumor progression and immunosuppression, highlighting the potential of targeting CAF histone lactylation as a therapeutic strategy for CRC.

Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.

There is currently no consensus on long-term risk stratification for metachronous gastric neoplasms (MGNs) occurring beyond 5 years following endoscopic submucosal dissection (ESD).This study aimed to investigate the time-dependent changes in predictive factors for MGN after curative ESD for early gastric cancer (EGC) and analyze the clinicopathological features of late MGNs. We retrospectively reviewed patients who underwent ESD for early gastric neoplasms between March 2005 and June 2020. MGN was defined as a new gastric neoplasm detected at a different site >12 months following ESD. Survival data were collected and analyzed using multivariable and time-split Cox hazard regression models. Among 5,571 patients treated with ESD, 876 were included with a median follow-up of 58 months. The cumulative incidence of MGN was 10.79% at 5 years and continued to accumulate beyond 5 years (26.65% at 10 years). All MGNs were stage I and there was no gastric cancer-related mortality. Cox regression analysis identified family history of gastric cancer (adjusted hazard ratio [aHR] 2.12, 95% confidence interval [CI] 1.32 - 3.41) and extensive intestinal metaplasia (aHR 6.50, 95% CI 3.73 - 11.36) as independent predictors of MGN. Histological upgrade was not associated with MGN during the first 5 years but emerged as a significant risk factor in the late period (interaction P value = 0.005). MGNs may develop even beyond 5 years following ESD with curative resection in patients with EGC. These findings highlight the long-term risk of MGN after ESD, providing a framework for clinical risk estimation.

For more than 10 years, the US Preventive Services Task Force has recommended annual lung cancer screening (LCS), but adherence to annual screening remains low. To test 2 multilevel, patient-centered interventions to increase adherence to guideline-concordant annual LCS. A pragmatic 2 × 2 factorial randomized clinical trial was conducted at Kaiser Permanente Washington among patients who completed LCS with normal findings from November 21, 2022, to April 5, 2024. The date of last follow-up was July 4, 2025. Data were analyzed from July to December 2025. The 4 arms included usual care, health communication, Stepped Reminders, or both interventions. The health communication intervention addressed patient screening knowledge barriers with print and video messaging. The Stepped Reminders intervention pended LCS scan orders for primary care physicians (PCPs) and sent outreach to patients to remind them to schedule scans. Both interventions were facilitated by a system-level LCS coordinator with electronic health record registry to deliver interventions. The primary outcome was completion of screening low-dose computed tomography (LDCT) or chest CT 9 to 15 months after index LDCT. All participants eligible for annual screening were included in the modified intent-to-treat analysis. Participants were censored due to lung cancer diagnosis, death, early LDCT or chest CT, or disenrollment from the health plan. Among 1837 trial participants, the mean (SD) age was 66.3 (6.5) years; 897 (48.8%) were female and 940 (51.2%) were male; 17 (1.0%) were American Indian or Alaska Native, 47 (2.7%) were Asian, 55 (3.1%) were Black, 10 (0.6%) were Native Hawaiian or Other Pacific Islander, 1560 (88.7%) were White, 37 (2.1%) were multiracial, and 32 (1.8%) were another race; and 875 (47.6%) were currently using tobacco. A total of 459 were randomized to the usual care group, 460 to the health communication group, 460 to the Stepped Reminders group, and 458 to the both interventions group. Adherence to annual screening was 4.7 percentage points lower in those who received the health communication intervention relative to those who did not (59.2% [476 of 804] vs 63.3% [516 of 815]; relative risk, 0.93; 95% CI, 0.86-1.00; P = .04) and 27.7 percentage points higher in those who received the Stepped Reminders intervention relative to those who did not (75.5% [604 of 800] vs 47.4% [388 of 819]; relative risk, 1.59; 95% CI, 1.47-1.72; P < .001). The Stepped Reminders intervention improved screening rates significantly more among participants currently using tobacco (received Stepped Reminders, 281 [73.0%]; did not receive Stepped Reminders, 160 [41.2%]; risk difference, 32.3 percentage points; 95% CI, 25.9-38.8) compared with former users (received Stepped Reminders, 323 [77.8%]; did not receive Stepped Reminders, 228 [52.9%]; risk difference, 24.1 percentage points; 95% CI, 18.1-30.0) (P for interaction = .03). In this randomized clinical trial, appropriately timed multilevel reminders directed to PCPs to order and patients to schedule LDCT scans were effective at improving annual LCS adherence in programs led by PCPs. ClinicalTrials.gov Identifier: NCT05747443.

Glucuronide prodrug strategies may enhance target specificity and reduce the toxicity of PARP inhibitors, but no clinical evaluation has been performed. We evaluated TSL-1502, a novel glucuronide prodrug of a PARP inhibitor, in a randomized, open-label, phase 2 study at 28 sites in China (NCT05420779). Eligible patients were women aged 18-75 years with HER2-negative locally advanced or metastatic breast cancer and germline BRCA mutations. Patients were assigned randomly (2:2:1) to receive TSL-1502 at 350 mg or 500 mg once daily or the investigator's choice of chemotherapy (eribulin, capecitabine, or vinorelbine) in 3-week cycles. Sixty-three patients were enrolled between August 18, 2022, and March 5, 2024. According to the Independent Review Committee assessment, the objective response rates were 36.0% (95% CI, 18.0-57.5) in the 350 mg group, 55.6% (95% CI, 35.3-74.5) in the 500 mg group, and 40.0% (95% CI, 12.2-73.8) in the chemotherapy group. The median progression-free survival times were 5.6 (95% CI, 4.0-8.2), 8.8 (95% CI, 5.7-not assessable [NA]), and 9.2 (95% CI, 1.38-NA) months, respectively, and the overall survival times were 17.4 months (95% CI, 9.1-NA), not reached (95% CI, 16.9-NA), and 19.8 months (95% CI, 9.2-NA), respectively. Grade ≥3 treatment-related adverse events occurred in 60.0%, 59.3%, and 80.0% of patients, with anemia most common in the TSL-1502 group and neutropenia most common with chemotherapy. No treatment-related deaths occurred. TSL-1502 at 500 mg showed promising antitumor activity and a manageable safety profile, supporting further clinical development.

Spatial biomarkers are critical for precision oncology but remain challenging to systematically discover due to the complexity of whole-slide images. We present PathPrism, an interpretable AI framework for spatial biomarker discovery and virtual experimentation. Unlike black-box models, PathPrism encodes tissue architecture into pathologically informed spatial features, enabling transparent modeling of prognosis, molecular alterations, and therapy response. Applied to 7,000 patients with colorectal cancer across 11 cohorts, PathPrism uncovered hundreds of biomarkers predictive of survival, MSI, BRAF, and TP53 mutations, and stratified chemotherapy benefit in stage II/III disease. Building on these interpretable findings, PathPrism uses large language models as auxiliary tools to generate hypotheses grounded in spatial semantics. We further introduce VirtualWSI, a platform for semantic perturbation within an interpretable spatial biomarker atlas. PathPrism provides a scalable and interpretable framework for spatial biomarker discovery.

Pancreatic ductal adenocarcinoma is characterized by a fibrotic and metabolically active tumor microenvironment where cancer-associated fibroblasts (CAFs) mediate metabolic crosstalk, extracellular matrix (ECM) remodeling, and immune regulation. However, the metabolic and spatial heterogeneity of CAFs remains incompletely understood. We integrated spatial transcriptomics and spatial metabolomics data from PDAC tissues and performed SpatialGlue-based multimodal clustering to define CAF subtypes. To characterize metabolic communication, we developed an optimal transport (OT)-based metabolic inference framework to quantitatively model metabolite association between CAFs and tumor cells. Subtype-specific features were independently validated using an independent spatial metabolomics cohort and multiplex immunofluorescence (mIHC) staining. Furthermore, these features were correlated with clinical outcomes via TCGA-PAAD deconvolution. Spatial multi-omics integration identified three robust CAF subtypes with distinct signatures. OT analysis revealed differential metabolic interactions: CAF_C0 mediated amino acid/peptide transfer, CAF_C1 was the primary source of lipids, while CAF_C2 exhibited limited metabolic association but stronger immune and ECM signaling activity. Deconvolution confirmed that CAF composition was strongly associated with prognosis; CAF_C2 enrichment predicted poorer survival and gemcitabine resistance, whereas a higher CAF_C0/CAF_C1 balance correlated with improved outcomes. By combining spatial multi-omics with OT-based modeling, this study delineates metabolically and spatially distinct CAF states with clinical relevance. Our findings suggest CAFs act as both metabolic donors and immune-ECM regulators, providing new insights into stromal reprogramming and potential subtype-specific therapeutic targets in PDAC.

Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common immune-related adverse event associated with camrelizumab and has been linked to favorable outcomes. We conducted a pooled analysis of two phase III randomized trials, ESCORT (NCT03099382) and ESCORT-1st (NCT03691090), to evaluate the clinical characteristics and prognostic relevance of RCCEP in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving camrelizumab-based therapy. A total of 526 patients treated with camrelizumab, either alone or in combination with chemotherapy, were included. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to RCCEP status. Inverse probability of treatment weighting (IPTW) was applied to adjust for baseline imbalances, and a 2-month landmark analysis was performed to reduce lead-time bias. Overall, 420 patients (79.8%) developed RCCEP, mostly grade 1-2 (99.0%), with no RCCEP-related treatment discontinuations. The median onset was 1.18 months, and the duration was 3.12 months. RCCEP-positive patients showed a higher ORR (52.4% vs. 26.4%), longer PFS (5.55 vs. 1.94 months; HR = 0.45), and OS (13.40 vs. 6.11 months; HR = 0.47), consistent after landmark analysis. These findings suggested that RCCEP was frequent yet manageable and may serve as a potential on-treatment biomarker of camrelizumab benefit in ESCC.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, highlighting the need for improved non-invasive biomarkers for early detection and prognostic evaluation. tRNA-derived fragments (tRFs) have emerged as regulatory non-coding RNAs in cancer, but their biological and clinical significance in GC remains unclear. To evaluate the diagnostic, prognostic, and biological significance of tRF-28-ZJ47D112Z4DZ (tRF-28) in GC and investigate its underlying molecular mechanism. tRF-28 was identified using a stepwise screening strategy, and an absolute quantification assay was established for plasma detection. Receiver operating characteristic (ROC) analysis, survival analysis, and Cox regression models were used to evaluate its clinical significance. Gain- and loss-of-function studies in GC cells, together with xenograft overexpression models, were performed to investigate its biological functions. RNA immunoprecipitation, dual-luciferase reporter assays, rescue experiments, and immunohistochemistry were used to explore the underlying mechanism. Plasma tRF-28 levels progressively decreased from healthy controls to precancerous lesions and GC patients. tRF-28 demonstrated diagnostic value for precancerous lesions (AUC = 0.713) and showed moderate but reproducible diagnostic performance for GC in both the training and validation cohorts (AUC = 0.762 in the training cohort). Reduced plasma tRF-28 levels were associated with poor differentiation, deeper invasion, and unfavorable overall survival, and multivariate Cox analysis identified tRF-28 as an independent protective prognostic factor. Functionally, tRF-28 inhibited GC cell proliferation, colony formation, invasion, migration, and cell cycle progression while promoting apoptosis. Mechanistically, tRF-28 associated with Argonaute 2 (Ago2) and directly targeted the 3' untranslated region of CCND1, thereby suppressing the Cyclin D1/CDK4/p-Rb signaling pathway. Xenograft studies further confirmed its tumor-suppressive effect in vivo. tRF-28 suppresses GC progression through regulation of the CCND1-associated cell cycle pathway and may serve as a complementary plasma biomarker for GC diagnosis and prognostic assessment.

Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer that leads to severe neurologic symptoms and a poor prognosis. Current treatment options, including radiation and intrathecal chemotherapy, offer limited efficacy and are associated with significant toxicity. Generally, systemic therapy in LMD poorly penetrates the blood-brain barrier (BBB). Leveraging the L-type amino acid transporter 1 (LAT1) represents a unique therapeutic strategy, as LAT1 facilitates transport of medications across the BBB, and is also highly expressed in metastatic cancer cells. QBS72S is a first-in-class BBB-penetrant bifunctional molecule targeting overexpression of LAT1 to selectively eliminate cancer cells. It has shown preclinical efficacy in a mouse model of breast cancer LMD. This Phase 2a, single-arm, open-label clinical trial (NCT05305365) investigated the safety, cerebrospinal fluid (CSF) concentration, pharmacokinetics, and preliminary efficacy of QBS72S in participants with breast cancer brain metastases. Secondary endpoints included progression-free survival, overall survival, and duration of response. Correlative analyses included LAT1 immunohistochemistry and CSF cell-free RNA sequencing. In this analysis, we report results from breast cancer patients with LMD (n = 10) treated with QBS72S. QBS72S was reliably detected in CSF, adequately tolerated, and two participants exhibited long-term radiographic stability or improvement lasting 6-7 months. These early findings support further investigation of QBS72S as a targeted therapy for LMD, addressing an urgent unmet need in metastatic breast cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with chemotherapy response evaluation currently relying on the Response Evaluation Criteria in Solid Tumors (RECIST). However, RECIST inadequately captures the unique biology of PDAC, particularly stromal fibrosis-induced radiographic pseudoprogression. We developed and externally validated a multivariable prognostic prediction model, the chemotherapy Progression Decision (cPD) score, integrating biological markers and imaging metrics to guide therapeutic decision-making after the first RECIST assessment. This multicenter retrospective study enrolled 616 PDAC patients across three cohorts: the Training Cohort (n = 155), Validation Cohort 1 (n = 263), and Validation Cohort 2 (n = 198). Multivariable Cox regression identified four independent prognostic predictors: neutrophil-to-lymphocyte ratio, baseline carbohydrate antigen 19-9, tumor maximum cross-sectional rate change ratio, and emergence of new lesions. These were integrated into an integer-based score (8-13 points) stratifying patients into good prognosis (GP), poor prognosis (PP), and critical prognosis (CP) groups. The cPD model demonstrated robust discrimination and calibration, with significant survival differences across groups in all cohorts. Notably, the cPD score identified a subset of patients (GP and PP groups) for whom continuing the original chemotherapy yielded significantly better survival than switching regimens, even when RECIST classified the disease as progressive.

Electronic patient-reported outcome (PRO) monitoring has shown benefits in advanced cancer, but data specific to metastatic breast cancer (mBC) remain limited. Fatigue is a common, clinically important, and functionally impairing symptom in mBC, making it a patient-centered target for electronic PRO monitoring. To determine whether digital PRO monitoring with alert-based responses reduces fatigue in patients with mBC. This multicenter randomized clinical trial was conducted from May 2021 to February 2024, with 12 months of follow-up, at 52 breast cancer centers in Germany and included women aged 18 years or older with mBC who were receiving systemic therapy at any point in the metastatic disease course, had a life expectancy of longer than 3 months, were able to read German, and had smartphone access. Data analysis started in February 2024 and lasted 6 months. The intervention group completed weekly PRO questionnaires via a smartphone using validated short forms from the European Organization for Research and Treatment of Cancer computerized adaptive testing core item bank. Automated alerts based on predefined PRO deterioration were emailed to trained local nurses or physicians, who contacted patients by telephone within 48 hours. The control group received usual care with quarterly PRO questionnaires and no alerts. The primary outcome was fatigue at 6 months. Secondary outcomes included fatigue, physical functioning, and quality of life over 12 months. PROs were reported as standardized T scores. Of 2008 patients screened, 924 (46.0%) were randomized, and 909 (45.3%) were included in the primary analysis (median age, 50 years [range, 19-83 years]). Baseline mean (SD) fatigue T scores were 57.6 (9.5) in the intervention group and 60.2 (9.0) in the control group (P < .001), with baseline PROs assessed after randomization but before group-specific follow-up began. At 6 months, adjusted mean fatigue was 54.5 (95% CI, 53.7- 55.4) vs 59.9 (95% CI, 59.0-60.8), yielding a mean difference of -5.4 points (95% CI, -6.6 to -4.1; P < .001), exceeding the minimal clinically important difference (MCID) of 3.3 points. At 6 months, physical functioning was higher in the intervention group (mean difference, 4.0; 95% CI, 2.6-5.4), exceeding its MCID (3.2), whereas the between-group difference in quality of life was 0.8 points (95% CI, 0.02-1.5), which was less than the MCID of 2.9. This randomized clinical trial found that digital PRO monitoring was associated with clinically meaningful reductions in fatigue and improved physical functioning. These findings support further evaluation of alert-based PRO monitoring in routine oncology care. German Clinical Trials Register: DRKS00024015.

Adaptive therapy is an evolution-based treatment paradigm that has been shown to delay resistance in prostate cancer through treatment breaks that control, rather than minimize, tumor burden. However, patient responses are highly heterogeneous, and there is a significant unmet clinical need for biomarkers to personalize treatment scheduling. To develop and retrospectively validate mathematical biomarkers that predict time to progression (TTP), mean daily dose, and overall survival (OS) under adaptive therapy from first-cycle prostate-specific antigen (PSA) dynamics. This retrospective modeling and validation study used longitudinal, nonrandomized clinical trial data from 2 independent cohorts: 40 patients with castrate-sensitive prostate cancer (CSPC) (June 1996 to September 2006) and 13 patients with metastatic castrate-resistant prostate cancer (mCRPC) (April 2015 to January 2022). A 2-population differential equation model was used to describe the overall tumor growth through the competing dynamics of drug-sensitive and drug-resistant cells. The statistical analysis was conducted from January 2025 to May 2026. Patients received either intermittent androgen deprivation therapy (for CSPC) or adaptive abiraterone acetate (for mCRPC). The initial treatment cycle served as the exposure period to extract longitudinal PSA kinetics. Mechanism-based mathematical biomarkers (adaptive therapy score, expected TTP, and expected mean daily dose) were derived from first-cycle PSA kinetics. Outcomes included in silico benchmarking experiments and retrospective validation against clinical TTP and OS. Performance was benchmarked against standard phenomenological PSA metrics (eg, PSA nadir, time to nadir, and doubling time). Overall, data from 53 patients across 2 clinical trials were included. In the CSPC cohort of 40 patients, the adaptive therapy score derived from first-cycle data was highly prognostic for prolonged clinical TTP (univariable hazard ratio [HR], 0.49; 95% CI, 0.31-0.76; P = .002). In the mCRPC cohort of 13 patients, the adaptive therapy score exhibited a strong rank correlation with clinical TTP (Spearman ρ = 0.76; P = .002) and was associated with prolonged TTP (HR, 0.41; 95% CI, 0.16-1.07; P = .07). Analysis of long-term survival data in the mCRPC cohort demonstrated that both the adaptive therapy score and expected TTP were significantly associated with prolonged OS, whereas standard empirical PSA metrics displayed no association with OS. In this modeling and validation study, mechanism-based mathematical biomarkers derived from the initial-cycle PSA dynamics accurately predicted patient-specific outcomes and survival, outperforming traditional phenomenological PSA monitoring. These accessible metrics could act as a mathematically informed decision support framework to stratify patients into personalized treatment protocols.

Patients with gastric cancer face substantial risk of recurrence after surgical resection. Molecular profiling of primary tumors may improve risk stratification to guide postoperative management. To identify genomic features of primary gastric tumors associated with disease recurrence and patterns of metastatic spread. This single-center cohort study took place at an academic quaternary referral center and included patients who underwent curative-intent resection of gastric adenocarcinoma from 2010 to 2024. Patients were classified by recurrence status and pattern of metastatic spread. Patients with gastric cancer (stages I to III) who underwent a margin-negative resection and had genomic sequencing of their primary tumor were included. Primary analysis excluded patients who had no evidence of disease with less than 2 years of follow-up. These data were analyzed from June 2025 through March 2026. Primary tumor specimens were sequenced using a targeted panel of cancer-associated genes (MSK-IMPACT). Correlation of disease-free survival and patterns of metastatic spread (hematogenous, peritoneal, or lymphatic) with primary tumor genomic profile. Among 438 patients who underwent complete oncologic resection, 377 had sufficient clinical follow-up or developed recurrence (median [IQR] age, 64 [55-71] years; 113 female [30%] and 264 male [70%]). Recurrence was identified in 179 patients, whereas 198 patients had no evidence of disease. In a multivariable analysis, alterations in KRAS (hazard ratio [HR], 1.54; 95% CI, 1.04-2.28; P = .03) and PIK3CA (HR, 2.15; 95% CI, 1.25-3.69; P = .006) were independently associated with worse disease-free survival. Tumors of patients with hematogenous recurrence had greater chromosomal instability (fraction genome altered, 0.11 vs 0.03; P = .001), whole-genome duplication (47% vs 15%; P = .02), and more frequent alterations of genes modulating cell cycle regulation (39% vs 6%; P < .001) compared with peritoneal recurrence. Bone metastasis arose from more genomically stable primary tumors (fraction genome altered, 0.005 vs 0.114; P < .001) and tumors with Lauren diffuse-type histology (36% vs 3%; P < .001) compared with other sites of hematogenous spread. This study identifies genomic alterations associated with disease-free survival and patterns of recurrence after resection of gastric cancer. These clinicogenomic risk factors may personalize postoperative surveillance strategies and inform perioperative treatment decisions.

The incidence of cancer in people with cardiovascular disease (CVD) is poorly understood. This study aimed to understand the sex differences in incident cancer and cancer-related mortality in people with and without CVD. Participants were drawn from the European Prospective Investigation into Cancer (EPIC)-Norfolk study and followed up for a median of 26.2 years. Participants were stratified by sex and incident CVD during follow-up. Cumulative cancer incidence was calculated for each group. Sex-specific lifetime risks of cancer were determined, accounting for competing risks of death. Cause-specific hazard ratios (HRs) were determined using Royston-Parmar models, adjusted for ethnicity and time-updated covariates, including deprivation index, cardiovascular risk factors, comorbidities, and medication. Participants' CVD status was updated throughout follow-up. A total of 22 534 participants were cancer-free at baseline (57% women; mean age 58.6 ± 9.3 and 59.5 ± 9.3 for women and men, respectively); 10 889 participants either had prevalent CVD at baseline or developed CVD during follow-up. Men had more comorbidities. The adjusted lifetime risk of incident cancer in CVD participants at age 75 was higher in men (17.3%) than in women (12.8%), with a significant cause-specific HR of 1.39 (99% confidence interval [CI] 1.25-1.53, P < .0001). Corresponding data for participants with no CVD were 10.2% for men and 8.2% for women, with an HR of 1.27 (99% CI 1.15-1.41, P < .0001 for men vs women). A similar trend exists for cancer-related mortality (HR 1.51, 99% CI 1.31-1.75, P < .0001 for men with CVD and HR 1.31, 99% CI 1.14-1.50, P < .0001 for men without CVD). This study showed an increased lifetime cancer risk and mortality in men compared with women, which was mediated by comorbid CVD.

Stress is associated with increased cancer morbidity and mortality. Here, we show that chronic stress accelerates glioma growth and reduces survival of tumor-bearing mice. Integrated multi-omics analysis of syngeneic glioma samples reveals stress-induced CD45+CD11b+C5aR1+ macrophages, termed stress-associated macrophages (SAMs). Using parabiosis experiments in mice, we demonstrate that SAMs are derived from bone marrow monocytes. Stress-activated sympathetic nerve promotes the differentiation of ADRB2+ bone marrow monocytes into SAMs, which can be antagonized by selective ablation of catecholaminergic nerves. Conditional knockout of C5ar1 in macrophages, or pharmacologic C5aR inhibition, reduces SAMs and attenuates stress-induced glioma tumor growth in vivo. SAMs exhibit elevated CD36 expression, leading to excessive intracellular lipid accumulation and peroxidization, dampening their phagocytotic capacity. SAMs abundance correlates with self-reported stress levels and portended prognosis in glioma patients. Collectively, these findings suggest that stress reprograms tumor immune microenvironment by inducing molecularly distinguished monocyte-derived macrophages, revealing potential opportunities for immune-based cancer therapies.

Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via FASN. Genetic and pharmacological inhibition of FASN significantly reduced tumor growth in a chicken embryo Chorio-allantoic Membrane model exposed to smoke. FASN inhibitors such as TVB-2640, currently in clinical trials, may represent an effective therapeutic strategy for smokers with bladder cancer exhibiting high FASN levels.

Pharmacological targeting of Signal Transducer and Activator of Transcription 3 (STAT3) in cancer has demonstrable antitumor efficacy. However, suitably potent, efficacious, and safe STAT3 inhibitors are scarce, and only a handful have entered clinical trials, limiting our knowledge of the extent of clinical benefit. Outcomes of recently completed trials in advanced cancers range from improved overall survival and complete responses in a cohort of patients with phosphotyrosine STAT3 positivity to partial responses and progressive disease in unselected patients. Advancements in oligonucleotide technologies and the integration of E3 ligase-specific proteolysis-targeting chimeras and molecular glue protein degrader strategies are accelerating the transition of STAT3 inhibitors into clinical testing. This review examines recent STAT3-targeted modalities and their preclinical and clinical activities. It concludes by underscoring the value of biomarker-informed approaches to optimize patient outcomes, combination therapies to improve clinical benefits, and artificial intelligence/machine learning tools to accelerate development.

Induction of ferroptosis is a potential strategy for treating cancer and improving the efficacy of immunotherapy. Ferroptosis is driven by excessive peroxidation of polyunsaturated fatty acid-containing phospholipids, suggesting that microenvironmental lipid metabolites may regulate ferroptotic sensitivity. By integrating single-cell and bulk transcriptomics from immunotherapy cohorts, we identified the prostaglandin (PG) pathway as closely associated with tumor ferroptosis and therapeutic efficacy. Further screening revealed PGF2α as a potent endogenous ferroptosis sensitizer. Mechanistically, microenvironmental PGF2α bound to ferroptosis suppressor protein 1 (FSP1) at alanine 295 (A295) and inhibited its enzymatic activity, leading to lipid peroxidation accumulation upon ferroptotic stimuli. Preclinically, PGF2α supplementation or FSP1 ablation enhanced tumoral ferroptosis, potentiated CD8+ T cell-mediated immunity, and suppressed tumor progression in immunocompetent mice. Moreover, PGF2α improved immunotherapy efficacy across multiple mouse models, including subcutaneous allografts, Braf/Pten-driven spontaneous melanoma, and humanized mice. Clinically, a high PGF2α activity-related transcriptomic signature correlated with elevated ferroptosis and improved patient survival. Collectively, these findings establish PGF2α as a pro-ferroptotic metabolite and propose that targeting the PGF2α/FSP1 axis may offer an effective cancer immunotherapeutic strategy.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by a dismal prognosis and insensitivity to immune checkpoint blockers (ICBs); however, the underlying mechanism remains elusive. This study aimed to identify tumour cell-intrinsic regulators that promote immune evasion and ICB resistance in PDAC. Multi-omics analysis and clinical cohort studies identified protein disulfide isomerase family A member 6 (PDIA6) as a regulator of the immune microenvironment. Flow cytometry, multiplex immunohistochemistry, electron microscopy and Glutathione S-Transferase (GST) pulldown assays confirmed that PDIA6 repressed PRKR-like endoplasmic reticulum kinase (PERK) activation and immunogenic cell death (ICD). Chromatin immunoprecipitation confirmed that KRASG12D and YY1 modulated PDIA6 transcription. LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-1-Cre (KPC) mouse models showed that PDIA6 inhibition improved ICB response. Multi-omics screening identified PDIA6 as a biomarker of CD8+ T-cell paucity and poor prognosis in patients with PDAC. High PDIA6 levels predicted poor ICB response in the PDAC cohorts. PDIA6 inhibition reprogrammed the immunosuppressive tumour microenvironment and hindered mouse PDAC growth in the presence of CD8+ T-cell, which is attributed to enhanced ICD. PDIA6 interacted with cysteine 453 of PERK, abrogating the disulphide bond-mediated dimerisation and activation of PERK, an ICD inducer. Oncogenic KRASG12D potently upregulated PDIA6 via YY1-mediated transcriptional activation. We identified a small-molecule inhibitor of PDIA6, PACMA31, and demonstrated that targeting PDIA6 with PACMA31 improved ICB efficacy in a PDAC mouse model with KRAS mutations. PDIA6, driven by KRASG12D, alleviates ICD and promotes immune evasion, functioning as a predictive biomarker to screen ICB-sensitive patients and a therapeutic target to improve ICB efficacy in PDAC with KRAS mutations.

Ferroptosis is an iron-dependent form of regulated cell death that has emerged as one of the mechanisms underlying cisplatin-induced nephrotoxicity. Here, we report an iron-chelating polymeric micelle for controlled cisplatin activation and ferroptosis suppression to address the above issue. The block copolymer, methoxyl polyethylene glycol-poly(glutamic acid) (mPEG-PGlu) was coupled with an iron chelator, deferiprone (Dfp) to generate the tailored amphiphilic conjugate, mPEG-P(Glu-Dfp) that could coordinate with activated cisplatin and self-assemble into micelles (Pt@MDfp). The cisplatin-loaded mPEG-PGlu micelles (Pt@MGlu) and free cisplatin were employed as controls. Upon endocytosis, the intracellular labile iron could replace cisplatin due to the higher affinity between Dfp and Fe2+. This coordination exchange resulted in controlled cargo release and suppressed lipid peroxidation and inflammation in renal tubular cells (HK-2). The proof-of-concept was also validated in the subcutaneous 4T1 mouse breast tumor model using plasma and urine biomarkers of ferroptosis, inflammation, and renal injury as the indices, which concurred well with the histological staining of kidney tissue and fibrosis assessment. Moreover, due to the controlled cargo activation, Pt@MDfp significantly enhanced the in vivo antitumor efficacy compared to Pt@MGlu and free cisplatin. Collectively, the coordination exchange approach is promising in controlled delivery of cisplatin for efficacy enhancement.

Epithelial-mesenchymal transition (EMT) mediated metastasis remains the primary contributor to cancer-related mortalities worldwide, highlighting the critical need for therapeutic strategies that simultaneously eradicate primary tumors and suppress metastatic progression. However, conventional photodynamic therapy (PDT), particularly oxygen-dependent type-II photosensitizers, suffers from hypoxia-limited efficacy and may even induce EMT under suboptimal treatment conditions. Herein, we report enhanced type-I reactive oxygen species (ROS)-generating nanoparticles (NPs) based on the coassembly of two structurally similar small molecules (TQTT-NO and TQTT-NH), integrating light-controlled nitric oxide (NO) release to synergistically inhibit tumor growth and EMT. By leveraging precise molecular structure matching, the coassembled NPs (TQTT-NO/NH NPs) enable efficient intermolecular electron transfer, as revealed by the photocurrent results and Gibbs free energy calculations, thereby favoring type-I ROS generation under white-light irradiation while simultaneously triggering on-demand NO release. The developed TQTT-NO/NH NPs effectively suppress transforming growth factor-β (TGF-β)-induced EMT, inhibit cancer cell migration and invasion in vitro, and markedly reduce primary tumor growth and lung metastasis in a murine tumor model under light activation. Overall, this work establishes a generalizable molecular coassembly strategy for enhancing type-I PDT and EMT regulation, offering a promising paradigm for next-generation antimetastatic phototherapeutic platforms with translational potential.

SETD2-mediated H3K36me3 reprogramming is involved in homologous recombination (HR) repair; however, the dynamics of this repair process remain unclear. Here, we report that the scaffold protein menin, encoded by the Men1 gene, plays a crucial bridging role in H3K36-mediated HR repair. Genetic ablation of Men1 resulted in spontaneous lung carcinogenesis and was accompanied by severe genomic instability. Mechanistically, menin directly recognizes histone H2A.X via its Val371-Gln400 motif, and DNA damage markedly promotes the specific interaction between menin and γH2A.X. Subsequently, SETD2 is recruited to DNA damage sites by menin and acts as a writer to catalyze H3K36me3 reprogramming at local chromatin. LEDGF, as a reader, recognizes the H3K36me3 marker and further recruits CtIP as an effector to perform DNA end resection, ultimately activating the RPA2/Rad51 pathway. Restoring H3K36me3 via pharmacological intervention rescued impaired HR repair in Men1-deficient cells, further validating that menin governs HR repair in an H3K36me3-dependent manner. The results of the present study provide the detailed molecular mechanism underlying the previously described functions of H3K36me3 remodeling in HR repair.

A high rate of metastasis remains a challenge for the treatment of adenoid cystic carcinoma (ACC), yet the underlying mechanism of lung metastasis remains elusive. By integrating single-cell RNA sequencing and bulk transcriptomics with multiplex immunohistochemistry, we identified a metastatic niche consisting of IL1B+ tumor-associated macrophages (TAMs), CD24+ luminal-like tumor cells, ACKR1+ endothelial cells (ECs) and HSPA1A+CD8+ T cells. Importantly, we revealed that IL1B+ TAMs play diverse roles in the processes of tumor cell intravasation and colonization, two fundamental steps supporting metastatic outgrowth. In primary lesions, IL1B+ TAMs release elevated levels of VEGFA and MMPs, thereby coupling sprouting angiogenesis with extracellular matrix remodeling to facilitate cancer cell intravasation. In metastatic lesions, IL1B+ TAMs bind to IL-1R1 on ACKR1+ ECs to upregulate the expression of the adhesion molecule SELP, which can attract CD24+ luminal-like tumor cells for lung colonization. IL1B+ TAMs also increase the stress response state of HSPA1A+CD8+ T-cell recruitment and induce T-cell exhaustion, thereby facilitating the survival of disseminated tumor cells. Mechanistically, MIF derived from CD24+ tumor cells increases the transcription of IL1B in TAMs. We also reported that the infiltration of IL1B+ TAMs increased steadily with increasing lung metastatic progression in mice bearing metastatic ACC cells. Elevated plasma IL-1β and VEGFA levels are associated with increased metastatic burden and poor overall survival in patients with ACC. Our findings reveal the critical role of IL1B+ TAMs in reshaping the metastatic tumor immune microenvironment and reveal a potential therapeutic vulnerability for metastatic ACC.

Triple negative breast cancer (TNBC), characterised by the lack of progesterone receptor, oestrogen receptor and HER2 overexpression, is the most aggressive breast cancer subtype and is typically associated with high rates of metastasis, recurrence and mortality. Despite recent advances in treatment options, such as the use of PARP inhibitors, immune checkpoint inhibitors and antibody-drug conjugates, lasting clinical benefit is limited, particularly in advanced disease. A key driver of relapse in TNBC is extensive inter- and intratumoral heterogeneity, largely sustained by self-renewing cancer stem cell (CSC) populations. These cells exhibit enhanced plasticity, immune evasion and resistance to cytotoxic drugs, enabling treatment failure and relapse. Growing evidence implicates aberrant activation of mitogen activated protein kinase (MAPK) signalling in CSC maintenance, epithelial-mesenchymal transition (EMT) and resistance to therapy in TNBC. While MAPK pathway inhibitors show limited efficacy in monotherapy, preclinical and clinical data suggest that their integration with existing treatment strategies may enhance therapeutic robustness, delay resistance and reduce recurrence. Targeting MAPK, in combination with other drugs that restrain CSC plasticity could represent a promising strategy to improve long-term outcomes in TNBC.

Inflammation is a pathogenetic driver of several pathological conditions, including cancer. The tumor microenvironment, which includes cellular, molecular, and structural components, is an essential component of cancer, involved in tumor promoting or controlling processes. In particular, inflammatory players contribute to the establishment of a tumor-promoting microenvironment, which affects all stages of tumor development, from initiation to metastasis, as well as response to therapy. The IL-1 system includes two large sets of structurally related ligands and receptors, with agonist or regulatory activity, playing non-redundant roles in inflammation and immunity. Each of them has specific functions in tissue homeostasis, inflammation, innate and adaptive immune responses, and potentially contributes to processes related to carcinogenesis and metastasis, or immune-mediated control of cancer cells. Depending on the context and cellular target, IL-1 family members may play dual roles in cancer, driving both pro- or anti-tumor processes. IL-1α and IL-1β can directly promote cancer cell proliferation, survival, and plasticity, in addition to contribute to the establishment of a pro-inflammatory environment that promotes tissue remodeling, cellular stress responses, and genomic instability. On the other hand, IL-1 is a lymphoproliferative and activating molecule in innate and adaptive responses, thus contributing to anti-tumor immune mediated responses. In addition, members of the IL-1 system act as regulators of mechanisms involved in cancer, including emergency hematopoiesis, trained immunity, and metabolism. Here, we will provide an overview of the IL-1 system in cancer and discuss the functional complexity of IL-1 family cytokines, which orchestrate both protective and pro-tumorigenic responses, by directly acting on cancer cells and by driving environmental stimuli which indirectly act on cancer cells.

Platelet-derived growth factors (PDGFs) and their cognate receptors (PDGFRα/β) play critical roles in breast cancer progression and metastasis. This review summarizes current evidence of PDGF ligand and receptor expression patterns, oncogenic functions, prognostic significance and therapeutic targetability, with a specific focus on small molecule inhibition. PDGF-PDGFR signaling is known to contribute to epithelial to mesenchymal transition, cancer stem cell maintenance, desmoplasia, angiogenesis, and immune modulation. Additionally, the four PDGF ligands have distinct oncogenic functions. PDGFA and PDGFB have been implicated in breast cancer associated brain metastasis, while PDGFC has been shown to play a crucial role in fibroblast activation. PDGFD, while less studied, may activate epithelial to mesenchymal transition in breast cancer. High expression of PDGFA, PDGFB, PDGFC, and stromal PDGFRβ correlate with poor patient survival, highlighting their potential as candidate biomarkers. We specifically focus on evaluating current therapeutic strategies which target the PDGF-PDGFR axis, including neutralizing antibodies, aptamers, and small molecule inhibitors, which show preclinical promise but limited clinical success in breast cancer to date. We discuss future research directions with emphasis on identifying selective inhibitors, utilizing PDGF-PDGFR signaling components for patient stratification, and combination with immunotherapies.

Cancer metabolism is characterized by profound reprogramming, yet the mechanisms enabling rapid and precise adaptation remain incompletely understood. This review establishes post-translational modifications (PTMs) as the central processing unit of oncogenic metabolic reprogramming. PTMs execute a conserved three-tiered regulatory logic: they interpret oncogenic and environmental signals, command metabolic flux, and cement malignant phenotypes through epigenetic and feedback mechanisms. We systematically demonstrate how this PTM-driven logic governs key pillars of cancer metabolism-glucose, lipid, amino acid, and nucleotide utilization-and extends its command to critical cell fate execution programs, including mitochondrial dynamics, autophagy, and ferroptosis. Furthermore, we delineate how PTMs act as master regulators of immunometabolic reprogramming within the tumor microenvironment (TME), directly linking tumor metabolism to T cell exhaustion, myeloid cell polarization, and immune evasion. By integrating recent advances on the determinants and crosstalk of PTM networks, we describe how metabolic plasticity and heterogeneity are encoded at the PTM level, with metabolic gradients shaping distinct "PTM geographies" within tumors. Finally, we translate these insights into clinical prospects, highlighting PTM-based biomarkers, PTM-targeted drugs and emerging therapeutic strategies, including targeted protein degradation, PTM-targeted vaccines and dietary interventions. Deciphering this PTM-encoded program reveals a new landscape of therapeutic vulnerabilities, shifting the paradigm toward rationally targeting the fundamental computational logic that sustains tumors.

In a recent Cell paper, Maurais et al.1 show that genomic instability drives human cells to transfer fragmented chromosomes to neighbors via tunneling nanotubes (TNTs), with heritable functional consequences, raising fundamental questions about intercellular communication, genome surveillance, and cancer evolution.

Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the genetic and epigenetic drivers underlying this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis-derived organoids. Integrative RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs. Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5- cell generation. This reprogramming is mediated by the direct repression of HNF4A and increased H3K27ac and occurs independently of SOX17. Together, these findings identify GATA6 loss as a central regulator of multilineage plasticity that drives liver metastasis in CRC.

Primary and metastatic lesions share similar biological properties despite existing in different microenvironments. A better understanding of the mechanisms underlying the maintenance of phenotypic homogeneity in heterogeneous microenvironments could help identify strategies for suppressing metastasis. Here, we found that mechanical memory enabled tumor cells to resist biomechanical stress and sustain malignant traits. Matrix stiffness activated the RhoA-ROCK1 signaling pathway, leading to actin cytoskeletal remodeling and suppression of mitochondrial fission. The dysregulation of mitochondrial dynamics enhanced fatty acid β-oxidation, leading to the accumulation of acetyl-CoA and subsequent histone hyperacetylation. The stiffness-mediated epigenetic reprogramming was mitotically heritable, allowing progeny cells to retain a proliferative advantage after detachment from stiff environments. Inhibition of RhoA-ROCK1 disrupted mechanical memory, thereby reducing metastasis. These findings suggest that targeting mechanical memory may be a strategy for preventing metastasis.

Tumor radioresistance is a leading cause of radiotherapy failure. This study presents a facile strategy for enhancing tumor radiosensitivity using a covalent organic framework (COF) constructed within cells. Upon cellular internalization, acetamide and iodoacetal precursors undergo hydrolysis to form amine and iodoaldehyde monomers that spontaneously polymerize and crystallize within the lysosomes. This intracellularly generated iodine-rich COF (in situ UM-113) possesses an ordered structure that effectively facilitates radiation energy deposition, producing localized reactive oxygen species and amplifying DNA damage. In vitro and in vivo, in situ UM-113 suppresses tumor growth by triggering both ferroptosis and mitotic catastrophe. This strategy bypasses the complex synthesis and purification steps required for conventional nanomedicine. Thus, in situ COF construction is a promising strategy for enhancing cancer radiotherapy, offering a modular platform for the intracellular synthesis of functional bionanomaterials.

Air pollution is a leading environmental cause of lung cancer, yet the underlying biological pathways remain poorly understood. Identifying circulating biomarkers that capture early molecular responses may clarify how air pollutants contribute to carcinogenesis and help identify individuals at elevated risk. We conduct a prospective nested case-control study within two Cancer Prevention Study cohorts, profiling more than 1100 metabolites in pre-diagnostic plasma samples from 1357 participants. Residential concentrations of six major air pollutants are estimated at the time of blood draw. Here we show that eight circulating metabolites are associated with both air pollution exposure and subsequent lung cancer risk. Four metabolites, including γ-glutamylglutamine, phenylacetylglutamate, N-(2-furoyl)glycine, and 4-vinylguaiacol glucuronide, significantly mediate associations for particulate matter and ozone (adjusted q-value < 0.2). These findings suggest that air pollution may promote lung cancer partly through metabolic pathways related to inflammatory and oxidative processes, providing key insights into potential mechanisms and targets for prevention.

Circulating tumor cells (CTCs) are critical biomarkers for cancer prognosis and treatment monitoring, yet their detection remains challenging due to low abundance and phenotypic heterogeneity. Herein, we developed a dual-aptamer-conjugated electrochemical cytosensor using an in situ catalase (CAT)-encapsulated nanozyme CAT@Fe(SS)MOF-EpCAM/MUC1 (CMA) with a core-shell structure (64.8% catalase encapsulation efficiency) and magnetic nanoparticles Fe3O4-EpCAM/MUC1 (FA) for highly specific CTC capture. The CMA probe achieved 85.5% aptamer grafting efficiency and exhibited enhanced peroxidase (POD)-like activity through CAT-Fe(SS)MOF synergistic catalysis, significantly amplifying the differential pulse voltammetry (DPV) signal. The cytosensor achieved a detection limit of 2 cells/mL in 1 mL of whole blood, taking 95 min, with a wide linear range from 2 to 40 cells/mL. It demonstrated high specificity toward dual-antigen-expressing CTCs and showed promising clinical utility in discriminating lung cancer patients from healthy donors. The system demonstrated good anticoagulant properties, hemolysis rates of <5%, and IC50 values of 558 μg/mL (CMA) and >700 μg/mL (FA) for RAW264.7. This novel electrochemical cytosensor offers a portable and efficient platform for CTCs detection, thereby paving the way for its meaningful integration into clinical practice.

Extensive-disease small-cell lung cancer (ED-SCLC) is an aggressive disease with limited effective therapeutic options. Clinical trials suggest an additive effect of chemotherapy and immunotherapy in SCLC, although the magnitude of benefit seems to be limited. Considering the prolonged peripheral persistence of anti-PD-(L)1 blockade, we wanted to investigate the impact of prior immunotherapy exposure on the efficacy of second-line chemotherapy. Using the Epidemio-Strategy and Medical Economics lung cancer national real-world database, we selected ED-SCLC patients diagnosed between 17 February 2010 and 4 December 2023 who had received at least two lines of treatment for a metastatic disease with platinum-based regimens in the first-line setting. Second-line real-world progression-free survival (rw-PFS) and overall survival (OS) were analyzed according to first-line immunotherapy exposure using a multivariable Cox proportional hazards model and a propensity score-weighted sensitivity analysis. The study included 2051 patients with ED-SCLC: 638 (30%) in the immunotherapy-pretreated group and 1413 (70%) who received only first-line chemotherapy. Multivariable analysis showed no significant difference in second-line median rw-PFS between immunotherapy-pretreated patients [2.9 months, 95% confidence interval (CI) 2.7-3.3] and chemotherapy-only pretreated patients (2.5 months, 95% CI 2.4-2.7) (hazard ratio 0.94, 95% CI 0.85-1.04, P = 0.21). Similar results were observed in the propensity score adjusted Cox regression sensitivity analysis. A longer median OS from the start of second-line treatment was observed in immunotherapy-pretreated patients (6.6 months, 95% CI 6.1-7.1 compared with 5.7 months, 95% CI 5.4-6.1, P = 0.03) although, this result has not been confirmed in a more contemporary cohort. This study showed no OS gain in second-line treatment among patients pretreated with immunotherapy compared with those who received chemotherapy alone as first-line treatment.

Liquid biopsy based on extracellular vesicle (EV) surface protein provides a non-invasive strategy for lung cancer detection and clinical stratification, yet its translation to point-of-care testing (POCT) is hindered by labor-intensive preprocessing and nonspecific background from contaminating proteins. Here, we report an acoustofluidic chip that works as an "acoustofluidic dynamic sieve," integrating on-chip staining, separation, enrichment, and detection into a sample-to-answer EV assay. Acoustic and flow fields synergistically generate localized vortices that selectively retain and concentrate EVs (>30 nm) while laminar flow removes smaller proteins. This on-chip purification ensures that fluorescence signals originate predominantly from captured EVs, achieving 125-fold signal amplification with high specificity. The platform completes multi-target surface protein analysis using less than 1.5 μL of plasma without off-chip purification, simplifying the workflow and reducing sample consumption. In clinical testing, 5-fold cross-validation distinguished lung cancer patients from healthy controls with 94.12% sensitivity, 93.33% specificity, and 93.75% accuracy. This acoustofluidic dynamic sieve strategy overcomes the specificity challenge in EV-based diagnostics and shows significant potential for clinical translation.

Across many solid tumor types, cancer-associated fibroblasts (CAFs) are abundant and heterogeneous, with distinct subpopulations exerting immunomodulatory functions. Here we identify a novel population of immunomodulatory CAFs (imCAFs) in primary lung adenocarcinoma and pulmonary metastases, characterized by cell adhesion molecule L1-like (CHL1) expression and enriched in immune regulation and chemokine signaling programs. Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3+ regulatory T (Treg) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3+ Treg cell recruitment and promoting an immunosuppressive microenvironment. CXCR3+ Treg cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3- counterparts. Genetic ablation of Cxcr3 in Treg cells or Cxcl9 in stromal cells reduces Treg cell accumulation, enhances CD8+ T cell activation and decreases tumor burden. Analogous CHL1+ imCAF-like fibroblasts in human non-small cell lung cancer colocalize with Treg cells, and elevated CHL1 expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF-CXCL9-CXCR3+ Treg axis as a promising therapeutic target.

Pulmonary delivery of lipid nanoparticle (LNP)-based mRNA vaccines offers a promising strategy for localized lung cancer immunotherapy, yet how distinct pulmonary administration routes determine cellular targeting and therapeutic efficacy remains poorly understood. Here, we systematically evaluate intranasal and intratracheal delivery of mRNA-LNP vaccines and reveal a route-dependent immunological mechanism governing lung-targeted tumor vaccination. Although intratracheal administration yields only a 2.6-fold increase in total pulmonary protein expression compared to intranasal delivery, it produces a striking 26.8-fold enhancement in functional mRNA transfection efficiency within alveolar macrophages, the dominant antigen-presenting cell population in the alveolar space. This selective targeting reprograms alveolar macrophages toward an activated antigen-presenting phenotype, promoting efficient antigen presentation, robust CD8+ T-cell responses, and superior prophylactic and therapeutic efficacy in pulmonary tumor models. Notably, local depletion of alveolar macrophages completely abolishes the antitumor protection conferred by intratracheal vaccination, establishing their indispensable role in mediating pulmonary mRNA vaccine efficacy. Together, these findings provide mechanistic insights into lung-targeted mRNA cancer vaccination driven by alveolar macrophage engagement, providing critical insights for the design of next-generation LNP-based nanomedicines for lung cancer immunotherapy.

KRAS is a central oncogenic driver in multiple solid malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, and colorectal cancer. Activating KRAS mutations, together with co-mutations and gene-dosage alterations, reprogram signaling pathways, cellular metabolism, and the tumor microenvironment, thereby promoting aggressive tumor behavior and therapeutic resistance. Despite recent advances, including KRAS G12C inhibitors and emerging agents targeting G12D, pan-RAS(ON), and nucleotide-free RAS, clinical responses remain limited in many KRAS-mutant contexts due to rapid and multifaceted resistance. This review aims to examine the mechanisms underlying resistance to KRAS-targeted therapies and to provide an integrated perspective on how adaptive tumor responses limit the durability of KRAS inhibition. Selective pressure from KRAS-targeted therapies drives adaptive tumor evolution through on-target alterations, rewiring of signaling networks, and non-genetic changes in cell state and the tumor microenvironment. This review synthesizes current knowledge on these resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies. By integrating recent preclinical and clinical advances, this work provides a comprehensive framework for understanding resistance and improving the durability of KRAS pathway inhibition in cancer.

Arsenic exposure is closely associated with lung carcinogenesis, but how cells transition from early stress buffering to later adaptive remodeling remains unclear. Stress granules (SGs) are key cytoplasmic condensates formed during acute stress, yet whether arsenic-responsive circular RNAs (circRNAs) participate in this process in non-small cell lung cancer (NSCLC) is poorly understood. Here, we identified hsa_circ_0000118 as an arsenic-responsive circRNA that was upregulated in both arsenic-exposed human subjects and arsenite-treated NSCLC cells. Silencing hsa_circ_0000118 impaired cell viability, promoted apoptosis, suppressed proliferation, and increased vulnerability to sustained arsenic stress. Mechanistically, acute arsenite exposure induced mitochondrial dysfunction and SG assembly before overt cytotoxicity. Under these conditions, loss of hsa_circ_0000118 increased SG susceptibility and delayed SG clearance during recovery. The RNA-binding protein quaking (QKI) acted upstream in this process, as QKI knockdown reduced hsa_circ_0000118 expression, weakened its association with G3BP1-related complexes, and phenocopied the SG-sensitive state. In contrast, under sustained arsenic stress, loss of hsa_circ_0000118 disrupted nuclear factor kappa B (NF-κB)-related adaptive output, characterized by accumulation of p105 and p65 but reduced downstream survival-related signaling. P65 also showed partial colocalization with G3BP1-positive granules after acute arsenite exposure, suggesting a possible spatial link between early SG remodeling and later NF-κB-related signaling dysregulation. Overall, hsa_circ_0000118 is associated with both acute SG dynamics and sustained NF-κB-related survival output in arsenite-treated NSCLC cells. These findings identify hsa_circ_0000118 as a candidate component of arsenic-associated stress adaptation.

In a recent study published in Cell Press Blue, Huang et al. show that deubiquitinase-dependent stabilization of POU2F3 (POU class 2 homeobox 3), primarily driven by USP2 (Ubiquitin-Specific Protease 2), sustains the growth of the small cell lung cancer (SCLC)-P subtype of SCLC, revealing a strategy to exploit transcription factor dependence by disrupting protein stability.

Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship-driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, restores E2F1-mediated apoptosis, and induces mitotic catastrophe. It exhibits broad-spectrum anticancer activity and synergizes with poly(ADP-ribose) polymerase (PARP) inhibitors in multiple cancer types and enhances osimertinib sensitivity in EGFR-mutated non-small cell lung cancer (NSCLC) cells. CS18 demonstrates efficacy in patient-derived breast cancer xenografts and overcomes osimertinib resistance in refractory NSCLC in vivo. These findings establish CS18 as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.

Targeted therapies have improved outcomes in EGFR-, KRAS G12C-, and BRAF V600E-driven non-small cell lung cancer (NSCLC), but acquired resistance is molecularly and spatially heterogeneous. Driver-specific algorithms and validated biomarkers underpin post-progression care. Determining pathway activity, causal dependency, and a tractable therapeutic vulnerability requires evidence beyond detecting an acquired alteration. We propose a lesion- and time-specific pathway-dependency framework centered on the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway and the PI3K-AKT-mTOR pathway. It distinguishes three provisional biological states: MAPK-dominant resistance, shared-input MAPK-PI3K reactivation, and a candidate PI3K-enriched/MAPK-low state. A clinical management branch encompasses histologic transformation, central nervous system-limited progression, oligoprogression, and diffuse polyclonal progression and may coexist with a biological assignment. Spatially discordant mechanisms support a mixed assignment, whereas insufficient evidence remains indeterminate. Biological assignment integrates contemporaneous lesion-level findings, clonality, histology, and exploratory pathway readouts; progression pattern guides the clinical branch. The framework complements genotype-based classification and may clarify when better-supported systemic, histology-directed, or local treatment should take precedence. Evidence remains uneven: some driver-specific interventions have established clinical evidence or clinically supported activity, whereas most downstream MAPK strategies and all approaches matched to the candidate PI3K-enriched/MAPK-low state remain investigational. Limited tissue availability, spatial heterogeneity, unstandardized assays, and combination toxicity constrain implementation. Prospective studies should determine whether a locked classifier adds predictive value beyond the initiating driver and acquired genomic alterations. Until prospective validation is available, the framework is best suited to mechanistic interpretation and trial design; routine treatment continues to rely on validated biomarkers and established clinical evidence.

Therapies targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer have substantially improved outcomes. Nevertheless, marked biological and clinical heterogeneity continue to drive variability in prognosis and treatment sensitivity in early-stage disease. While contemporary guidelines provide broad management frameworks, uncertainty remains when tailoring treatment intensity to individual patients. HER2DX is a genomic-clinical test developed to support individualized decision-making in stage I-III HER2-positive breast cancer by integrating tumor biology with key clinical variables, including tumor size and nodal status. The assay generates three clinically relevant outputs: a prognostic relapse risk score, a pathological complete response (pCR) score, and an ERBB2 messenger RNA expression score. Since its original development, a substantial body of new evidence has emerged. Large international individual-patient-level meta-analyses have demonstrated independent associations of the HER2DX risk score with survival outcomes and of the pCR score with pathologically documented response beyond standard clinicopathological factors. Translational studies further show that HER2DX captures complementary biological features, such as hormone receptor signaling, proliferation, HER2 pathway activation, and immune infiltration and organization, that are not fully reflected by conventional pathology. Prospective evaluations, including prespecified analyses from the ECOG-ACRIN EA1181 CompassHER2 pCR trial and a multicenter real-world decision-impact study in Spain, provide additional evidence regarding the potential clinical application of HER2DX in both neoadjuvant and adjuvant settings. This updated review synthesizes current evidence and discusses practical, scenario-based considerations for integrating HER2DX into routine clinical practice to help optimize treatment intensity in early-stage HER2-positive breast cancer.

Spatial proteomics technologies have transformed our understanding of complex tissue architecture in cancer but present unique challenges for computational analysis1. Each study uses a different marker panel and protocol, and most methods are tailored to single cohorts, which limits knowledge transfer and robust biomarker discovery. Here we present Virtual Tissues (VirTues), a general-purpose foundation model for spatial proteomics that learns marker-aware, multi-scale representations of proteins, cells, niches and tissues directly from multiplex imaging data. From a single pretrained backbone, VirTues supports marker reconstruction, cell segmentation and typing, niche annotation, spatial biomarker discovery and patient stratification, including zero-shot annotation across heterogeneous panels and datasets. In triple-negative breast cancer, VirTues-derived biomarkers predict anti-PD-L1 chemo-immunotherapy response2 and stratify disease-free survival in an independent cohort3, outperforming state-of-the-art biomarkers derived from the same datasets and current clinical stratification schemes.

In this study, superparamagnetic iron-carbon (Fe/C) nanoparticles (SPINs) engineered for alternating magnetic field (AMF)-based cancer therapy were synthesized using a co-precipitation approach with optimized precursor ratios. The resulting nanoparticles exhibited high magnetic performance, achieving saturation magnetizations of up to 149 emu/g, which are favorable for efficient AMF-mediated therapeutic activation. Consistent with this magnetic behavior, our previously published in vitro cytotoxicity studies demonstrated significant dose-dependent reductions in cell viability at relatively low nanoparticle concentrations, supporting their therapeutic potential. Based on these findings, in vivo AMF-mediated treatments were evaluated in DU145 prostate and MCF-7 breast cancer xenograft models using intratumoral SPIN injections at concentrations of 50 and 100 µg/mL. In the DU145 model, the 50 µg/mL dose produced gradual tumor regression, whereas the 100 µg/mL dose resulted in more rapid tumor reduction in responsive animals. Comparable dose-dependent therapeutic responses were observed in the MCF-7 model, with the higher SPIN concentration producing more pronounced tumor regression over the treatment period. Notably, thermal imaging revealed no detectable bulk heating during treatment, consistent with numerical modeling predictions, suggesting that the observed therapeutic efficacy occurred in the absence of conventional bulk hyperthermia. Collectively, these findings provide proof-of-concept evidence for achieving tumor regression without detectable bulk heating and support the potential of Fe/C SPINs as a promising platform for AMF-mediated cancer therapy. STATEMENT OF SIGNIFICANCE: • Alternating magnetic field (AMF)-driven superparamagnetic iron nanoparticles (SPINs) achieve significant tumor regression in two in vivo cancer models • Therapeutic effect arises from nanoscale magnetic dynamics, not bulk hyperthermia • Non-thermal mechanism challenges prevailing assumptions in magnetic hyperthermia • Findings establish a design paradigm for externally programmable nanotherapies.

Decidual protein induced by progesterone 1 (DEPP1), also known as DEPP or C10ORF10, was originally identified as a progesterone-induced protein in endometrial stromal cells. Over the past two decades, research has progressively elucidated its involvement in various biological processes such as energy metabolism, redox regulation, and cellular autophagy. Additionally, DEPP1 has been implicated in the pathogenesis of several diseases, including diabetes, atherosclerosis, ischemic cardiomyopathy, breast cancer, and colon cancer. In this review, we systematically summarise the research progress on DEPP1, with particular emphasis on its molecular mechanisms in the crosstalk between oxidative stress and autophagy. Its cellular localization and functional uniqueness are discussed within the context of the classical redox-autophagy regulatory network. Furthermore, key issues in DEPP1 research and its potential translational applications are discussed to provide insights and perspectives for future studies centred on DEPP1.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options. Although PARP inhibitor (PARPi) offers great promise in treating TNBC with deficiency in homologous recombination (HR), most TNBC patients are HR-proficient. Furthermore, acquired resistance to PARPi remains as a challenge. Thus, there is an unmet need to identify new therapeutic target for developing advanced TNBC treatment strategy. I-SceI reporter assay and alkaline comet assay were used to analyze the role of Smyca in HR repair. Ingenuity pathway analysis was used to identify upstream regulators of Smyca-regulated transcriptome. RNA immunoprecipitation and RNA pull down were used to examine Smyca-FOXM1 interaction. Chromatin immunoprecipitation followed by sequencing was performed to identify FOXM1 target genes that are regulated by Smyca. Chromatin isolation by RNA purification was used to determine Smyca loading onto the promoters of FOXM1 target genes. Patient-derived organoid and xenograft mouse models were performed to evaluate the effect of Smyca on chemoresistance. Nanoparticle-assisted gapmer antisense oligonucleotides delivery was used to target Smyca in vivo. Co-culture of CD3 + T cells with TNBC cells and syngeneic mouse model were used to examine the effect of Smyca-FOXM1 targeting on anti-tumor immunity. The long non-coding RNA Smyca is highly expressed in TNBC. We show that Smyca is induced by genotoxic agents to enhance HR repair. Mechanistically, Smyca binds FOXM1 and promotes the recruitment of FOXM1 to the promoters of a set of HR and nucleotide metabolism genes, thereby promoting their expression. Smyca ablation induces BRCAness in HR-proficient TNBC, thereby sensitizing these tumors to platinum or PARPi. Furthermore, targeting Smyca-FOXM1 complex in combination with platinum or PARPi activates cGAS/STING pathway and tumor immunogenicity to enhance anti-tumor immune surveillance. Clinically, Smyca expression in breast cancer patients correlates positively with therapy resistance and negatively with HR deficiency, interferon signature, and infiltration of anti-tumor immune cells. Our study identifies an unprecedented role of Smyca in HR repair to promote TNBC survival and immune evasion in response to therapy and suggests Smyca as a potential target for sensitizing TNBC to chemotherapy, PARPi, or immunotherapy.

Since the identification of PARP1/2 as synthetic lethal targets in BRCA-deficient breast cancer and the subsequent approval of catalytic domain-targeting PARP inhibitors, the landscape of PARP inhibitors has expanded to encompass a broader chemical tool kit. Beyond PARP1/2's canonical role in DNA repair, PARP inhibitors have revealed context-dependent PARP functions in anticancer immunity, viral infection, neurodegeneration, and cellular organization. These discoveries have motivated new strategies that extend past targeting catalytic domains. In this review, we highlight three emerging directions: (a) biological insights revealed by PARP1/2 inhibitors in oncology and other settings, (b) progress in developing inhibitors against PARP family members beyond PARP1/2, and (c) approaches that target noncatalytic domains or modulate PARP function through mechanisms such as interface disruption and targeted degradation. We conclude by outlining key next steps for advancing PARP pharmacology, including substrate mapping, utilizing rational polypharmacology, targeting ADP-ribose readers and erasers, and expanding structural coverage of PARP family proteins.

Circadian rhythms orchestrate physiological processes through molecular clocks, regulating up to 43% of genes and influencing breast cancer progression. This review synthesizes recent evidence linking circadian disruption-from shift work, light-at-night exposure, and social jetlag-to increased breast cancer risk and metastasis. Epidemiological studies, including large cohorts like the Nurses' Health Study III, show a 78% higher risk with long-term night shifts, mediated by hormonal disruptions and accelerated cellular aging. Molecular mechanisms reveal subtype-specific clock gene alterations: luminal tumors exhibit estrogen-driven dysrhythmia, HER2-positive tumors show signaling pathway disruptions, and triple-negative tumors feature epigenetic silencing. EMT, invasion, and niche preparation display temporal regulation, with chronodisruption promoting protumorigenic environments. Clinical evidence supports chronotherapy, timing treatments like chemotherapy and immunotherapy to circadian phases for enhanced efficacy and reduced toxicity. Biomarkers from wearables enable personalized interventions, addressing health disparities in shift workers. Integrating circadian biology into oncology promises transformative precision medicine, with ongoing trials validating chronotherapeutic protocols.

Exosomes have been valuable biomarkers for disease diagnosis, however their low abundance still presents challenge for clinical application. In this paper, we report an electrochemical biosensor that enables sensitive and specific detection of exosomes without the requirement of pretreatment steps and signal amplification. In this study, the designed multifunctional peptides are firstly conjugate with silver nanoparticles (AgNPs) through sulfhydryl groups to form Pep-AgNPs, and subsequently combine with exosomes via the targeting sequence. Under acidic conditions, protonation of the peptide termini induces electrostatic interactions with exosomal surfaces, driving the assembly of Pep-AgNPs@Exo-clusters. The loaded AgNPs then generate high electrochemical signals, while the enrichment of exosomes and AgNPs may further enhance detection sensitivity, affording a wide linear range (102-107 particles/μL) and an ultralow detection limit (44 particles/μL). The proposed biosensor has been successfully implemented in clinical serum samples from breast cancer patients and healthy individuals, demonstrating its potential for early diagnosis of the cancer.

Breast cancer following metastatic dissemination is associated with high mortality rates, severely threatening women's health. As principal mediators of intercellular communication within the tumor microenvironment, secretory autophagosomes (SAPs) propel breast cancer progression and metastasis by modulating the establishment of the pre-metastatic niche, thereby positioning them as highly promising biomarkers for breast cancer. However, the paucity of accurate and simplified quantitative tools has impeded the direct detection of circulating SAPs. This study presents a sensing platform that couples nanozyme cascade catalysis with a covalent organic frameworks (COFs)-derived nanohydrogel (CGNH) for precisely assessing trace-level SAPs. The AuNBP@PtPd-MoS2 nanozyme, via its stereoconfiguration and trimetallic synergy, recapitulates the dual enzyme-mimicking activities of GOx/CAT. Hence, it enables self-sustained interfacial charge transfer. As a signal probe, it efficiently accelerates self-cascade catalysis and electrochemical mass transfer. Additionally, CGNH creates an ideal interface for SAPs enrichment and cascade catalysis, featuring a hierarchical pore structure, a hybrid conductive network, and suitable biocompatibility. With self-assembled antifouling peptide nanoparticles (APNP) as a shielding barrier, the platform reliably detects SAPs in intricate biological matrices verified using cellular, murine and clinical specimens. Compared with conventional biomarkers, SAPs produce more informative readouts on disease progression. This electrochemical platform differentiates between benign and malignant breast diseases and healthy controls with high diagnostic accuracy (AUC = 0.962), especially for gray-zone differentiation and metastasis forecasting. This study offers new avenues for SAPs-based liquid biopsy to identify signs of breast cancer metastasis and is expected to become a reliable non-invasive tool for personalized breast cancer management.

The cGAS-STING pathway is an evolutionarily conserved DNA-sensing mechanism that triggers innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using complementary proteomic approaches, we report that Casein Kinase 1 alpha (CK1α) operates as a bimodal regulator of the cGAS-STING pathway. CK1α supports optimal DNA sensing by counteracting proteasome-dependent degradation of cGAS, which involves the Cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1α restrains signal propagation in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1α using molecular-glue degraders suppressed aberrant cGAS-STING-driven inflammation signaling in a chromosomally unstable triple-negative breast cancer cell line, while cooperating with a STING agonist to promote apoptosis in acute myeloid leukemia cells. Thus, CK1α's dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development.

Malignant gliomas are lethal brain tumors characterized by profound local immunosuppression and a radically remodeled myeloid landscape. Although these tumors mobilize resident microglia and infiltrating monocyte-derived macrophages, the mechanisms governing their phenotypic convergence and diversification remain elusive. Here, we integrated single-cell profiling and spatial transcriptomics of glioma-associated microglia in the GL261 model. We identified distinct microglial states that aligned with tumor architecture, most notably Cst7-expressing disease-associated microglia (DAMs) that aggregated at the tumor invasive margin and exhibited a conserved transcriptional signature shared across various central nervous system pathologies. Interferon-γ and toll-like receptor signaling sequentially tuned stage-specific DAM features, including transient MHC-II expression and sustained PD-L1 upregulation, thereby recalibrating the local immune equilibrium by reshaping bidirectional DAM-T cell interactions during glioma progression. Our findings highlight microglial state transitions as a stage-specific layer of immune regulation in glioma that shapes T cell fate and support targeting microglial plasticity to rebalance anti-tumor immunity.

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor with an unmet need for novel therapies. Immune checkpoint inhibitors have failed to prolong survival of DMG patients. In this study, we screened for immune checkpoint molecules in DMG, evaluated immunological responses to checkpoint targeting by co-culture assays and depletion of immune cells in vivo, studied the effects of CD155 silencing by whole-transcriptome analyses and performed in vivo treatments with Thiostrepton. In human and murine DMG cells, as well as primary brain tumor samples, we identified CD155 as the most highly expressed immune checkpoint. When murine DMG cells were co-cultured with CD8+ T cells, silencing of CD155 led to a marked increase in T cell-mediated killing. Strikingly, CD155-deficient DMG cells failed to grow in immunocompetent mice, and depletion of CD8+ T cells allowed these tumors to grow. CD155 also exerted cell-autonomous effects on tumor cells: silencing of CD155 led to induction of apoptosis of DMG cells and delayed tumor growth in immunodeficient mice. Transcriptomic analyses identified FOXM1 as a key target of CD155. Notably, FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo. Finally, treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting agent, delayed tumor growth and prolonged survival. These studies demonstrate that CD155 regulates immune evasion and tumor growth in DMG, and suggest that targeting CD155 could be a valuable two-pronged therapeutic strategy for this disease.

Chronic stress has long been associated with poor cancer outcomes, yet the mechanisms linking systemic stress responses to glioblastoma progression remain poorly understood. In this issue of Cancer Cell, Yang et al. identify a stress-induced brain-bone marrow axis that rewires monocyte differentiation toward pro-tumorigenic macrophages, revealing unexpected therapeutic opportunities in glioblastoma.

Glioblastoma (GBM) remains a lethal brain tumor with limited therapeutic efficacy from current standard care. The platelet-derived growth factor receptor alpha (PDGFRA) is a major oncogenic driver frequently amplified in gliomas. However, its high expression is paradoxically associated with improved prognosis in lower-grade gliomas, indicating a context-dependent role that is not fully understood. The regulatory mechanisms controlling PDGFRA protein stability represent a significant knowledge gap. In this study, we identify tripartite motif-containing 21 (TRIM21) as a previously uncharacterized E3 ubiquitin ligase for PDGFRA. We demonstrated that TRIM21 catalyzed K48-linked polyubiquitination specifically at lysine 606 of PDGFRA, directing PDGFRA for proteasomal degradation. Surprisingly, the oncogenic activity of TRIM21 was strictly dependent on PDGFRA expression. TRIM21 promoted malignant phenotypes specifically in PDGFRA-positive GBM cells, while exhibiting minimal or opposite effects in PDGFRA-negative cells. Mechanistically, TRIM21-mediated degradation of PDGFRA relieved a constitutive tumor-restraining function and simultaneously activated key downstream oncogenic pathways, including ERK, STAT3, and NF-κB, driving aggressive tumor progression. Clinically, elevated TRIM21 expression correlated with poor patient survival and confers resistance to both conventional radio-chemotherapy and the PDGFRA-targeted tyrosine kinase inhibitor imatinib in PDGFRA-high GBM. Our integrated analysis revealed an inverse correlation between TRIM21 and PDGFRA protein levels in patient specimens and highlighted TRIM21 upregulation as a feature of advanced disease. Collectively, these findings unveiled a crucial regulatory axis wherein TRIM21 switched PDGFRA from a context-dependent protective factor to an oncogenic driver and revealed TRIM21 as a prognostic biomarker and a therapeutic target for the PDGFRA-amplified subset of GBM.

Malignancies of the nervous system remain a critical challenge in oncology, contributing substantially to cancer-related mortality in children and adults. Their aggressive behavior is influenced by adhesion heterogeneity of the tumor cells, as distinct patterns of cell-to-cell and cell-to-matrix interactions shape tumor organization, invasion, and resistance to conventional treatments. Here, we investigate tumor adhesion dynamics in a 3D spherical cavity culture platform that enables the rapid and high-throughput formation of uniform spheroids for parallel morphogenesis, adhesion profiling, and drug screening. The morphogenetic patterns of human neuroblastoma and patient-derived glioblastoma observed in 3D cavity culture closely correlated with tumor aggressiveness, ranging from adhesive layers in benign tumor subtype to compact spheroids in malignant cells and irregular aggregates in highly invasive, cancer stem-like counterparts. These morphologies corresponded to adhesion profiles: aggressive cells displayed elevated N-cadherin with variable integrin, while compact spheroids maintained a balance of both molecules. Blocking N-cadherin with ADH-1 disrupted spheroid integrity, and combining ADH-1 with DOX yielded synergistic cytotoxic effects in malignant phenotypes, highlighting N-cadherin upregulation in tumor cells with higher aggressiveness in 3D culture. Overall, our dynamic 3D spherical cavity culture enables reproducible 3D adhesion phenotyping, providing a simple method for malignancy assessment and supporting adhesion-targeted therapeutic strategies for personalized medicine.

Single-cell-level resolution tumor therapy represents an advanced strategy against glioblastoma but lacks suitable theranostic agents. Here, we developed a spatiotemporal-switchable, two-dimensional (2D), bismuthene-based second near-infrared window (NIR-II) nanozyme. In this platform, the bismuthene scaffold simultaneously directed the assembly of indocyanine green (ICG) into ordered J-aggregates and anchored monodispersed platinum (Pt) atoms. The resulting J-aggregates acted as an optical antenna with a long-wavelength absorption peak at 895 nanometers and high photobleaching resistance of 78.0%, enabling the identification of single tumor cells with a resolution of 44.3 micrometers at 1350 nanometers for precise glioma resection. Postoperatively, the spatiotemporal-switchable function was activated for therapeutic intervention, in which the photothermal effect amplified the original efficiency of the catalase-like activity of Pt atoms by threefold, driving a surge in intracellular oxygen to combat tumor hypoxia. Upon 808-nanometer irradiation, the induced oxygen release in the tumor microenvironment amplified ICG-mediated photodynamic therapy, and combined with bismuthene-mediated photothermal therapy, it effectively inhibited residual tumors. In an orthotopic glioma mouse model, this approach minimized recurrence and achieved increased survival without inducing neurological or motor deficits. This work provides an atomic-level and molecular-level design blueprint for NIR-II nanotheranostic agents, paving the way toward clinical translation of single-cell-level precision medicine for brain malignancies.

Human psychoneuroimmunology research has demonstrated that stress, depression, and close relationships reliably shape immune and endocrine function in ways that matter for health. Across studies of examination stress, laboratory stressors, marital discord, cancer survivorship, and dementia caregiving, psychosocial adversity predicts more infections, weaker vaccine responses and faster erosion of vaccine protection, slower wound healing, heightened inflammation, and accelerated cellular aging. Depression also sensitizes immune function, producing larger inflammatory responses when individuals encounter stressors. Loneliness, low support, and distressed relationships can amplify stress reactivity and are linked to greater inflammatory and metabolic vulnerability, including postprandial inflammatory and endothelial responses. More recent work has extended these pathways to the gut microbiome and intestinal permeability (leaky gut), integrating microbial, neuroendocrine, and immune mechanisms. Collectively, the evidence supports a biobehavioral model in which social stress accelerates immune aging and increases risk for inflammation-related disease, while behavioral and nutritional interventions can modify these trajectories.

High dimension spatial technologies are broadly being used to map the cellular and molecular organization of human cancers including tumor antigens and drug targets. This has revealed extensive spatial heterogeneity of target proteins, but does not quantify drug distribution itself. Exposing additional complexities for drug targeting and delivery, Lu and colleagues recently applied highly multiplexed spatial proteomics to tumors from patients treated with fluorescently labeled antibody therapeutics. Quantifying drug penetration and distribution on cells of specific phenotypes, this approach identified compounding challenges that would limit therapeutic success as both target and therapeutic distribution are highly variable between patients and within individual tumors. Macrophage uptake, stromal barriers, vascularization differences, and epithelial permeability were all associated with altered antibody distribution. As expected, highly desmoplastic pancreatic cancers had poor drug delivery, and similar fibroblast and extracellular matrix (ECM) rich microenvironments were also identified in head and neck squamous cell carcinomas (HNSCCs) as broadly prevalent barriers to drug delivery. Providing a measurement strategy for single cell drug distribution, this work points towards opportunities to predict these barriers in precision medicine and design drugs that overcome them as a clinically impactful frontier.

By positioning phase separation between Kirsten rat sarcoma virus oncogene homolog (KRAS) lipidation and membrane signaling, Wang et al. unify distinct aspects of KRAS biology. They show that farnesylation drives cytoplasmic KRAS condensates that promote processing, trafficking, and signaling, establishing condensat formation as a new mechanism for controlling RAS activity.

miR-210-3p is a well-established hypoxia-induced microRNA that is commonly upregulated in a wide range of solid tumors, traditionally linked to mitochondrial repression and hypoxia-inducible factor (HIF) signaling. However, its functional role in cancer remains complex and highly context dependent. Here we perform a comprehensive pan-cancer transcriptomic analysis together with functional assays, revealing that miR-210-3p not only mediates classical hypoxic responses but also amplifies mitotic gene expression through activation of FOXM1. Mechanistically, this effect is shown to be dependent on HIF1α but not on HIF2α and, importantly, it has not been recapitulated by hypoxia alone. Notably, activation of the mitotic program is observed in breast cancer cells but not in head and neck squamous carcinoma models, highlighting a strong degree of context dependency across tumor types. In breast cancer cells, miR-210-3p overexpression enhances FOXM1 phosphorylation, upregulates kinetochore regulators, and induces mitotic defects, correlating with poor prognosis in aggressive tumors. Together, these findings position miR-210-3p as a molecular integrator linking pseudohypoxia to mitotic dysregulation, contributing to tumor aggressiveness by sustaining HIF activity and promoting mitotic stress. This dual functionality reconciles its paradoxical effects on proliferation and highlights its potential as a therapeutic target in cancers characterized by pseudohypoxia and mitotic abnormalities.

Targeted kinase inhibitors induce marked tumor regressions but are limited by the emergence of drug-tolerant residual disease and resistance. Although tumor-intrinsic and adaptive immune mechanisms have been extensively studied, a better understanding of the contribution of innate immunity to targeted therapy durability is needed to devise optimal treatment strategies. Here, we showed that natural killer (NK) cells constrain targeted therapy resistance and identified a regression-associated macrophage program that promotes NK cell recruitment. In immunocompetent melanoma models that recapitulate patient treatment trajectories, tumor regression was characterized by robust NK infiltration, which transitioned to an NK-excluded residual state preceding resistance. A regression-associated macrophage subset (F4/80hiCCL5⁺MHCII⁺CD63⁺) contributed to NK cell recruitment via CCR2/5 signaling. Genetic depletion of macrophages using LysM-cre;iDTR mice impaired NK cell infiltration. Pharmacologic inhibition of PTPN22, a negative regulator of immune activation, reprogrammed the residual tumor microenvironment, restored NK cell recruitment, and delayed resistance onset. Analysis of patient tumor datasets from melanoma and lung cancer revealed concordant NK dynamics during therapy, linking this innate immune program to clinical outcomes. These findings identify innate immune remodeling as a key contributor to targeted therapy durability and identify NK cell recruitment, promoted in part by regression-associated macrophages, as a therapeutically actionable node for extending durability of response across oncogene-driven cancers.

For patients with metastatic hormone-sensitive prostate cancer who achieve deep prostate-specific antigen responses with androgen deprivation therapy plus an androgen receptor pathway inhibitor, continuous treatment until progression may not be necessary. EORTC 2238 tests whether an intermittent strategy can safely reduce toxicity, improve quality of life, and lessen health care resource use.

While it has been reported that antioxidant selenoproteins are crucial for anti-ferroptosis in tumors, it remains unclear whether and how biosynthetic dysregulation of selenoproteins promotes resistance to ferroptosis. By bioinformatics analysis and in vitro confirmatory assays, we screened and identified selenophosphate synthetase 2 (SEPHS2), a key enzyme in a selenoprotein synthesis cascade, as a potential candidate for promoting anti-ferroptosis in tumors. We found that the expression of SEPHS2 was upregulated upon treatment with ferroptosis inducers. Knockdown of SEPHS2 inhibited tumor proliferation, migration and invasion, as well as attenuated selenoprotein biosynthesis to sensitize tumor cells to ferroptosis. Furthermore, our results demonstrated that activating transcription factor 4 (ATF4), a ferroptosis‑related transcription factor, might work as a direct upstream regulator to activate SEPHS2 transcription. Downregulation of ATF4 enhanced sensitivity to ferroptosis, whereas restoration of SEPHS2 expression rescued this effect, suggesting that ferroptosis resistance might be regulated by the ATF4/SEPHS2 axis. Notably, for the in vivo assay, knockdown of either SEPHS2 or ATF4 exhibited the optimal repression of tumor growth when combined with ferroptosis inducers. Thus, our findings highlight that inhibition of ATF4/SEPHS2 signaling might contribute as a novel adjuvant therapeutic strategy to improve the efficacy of ferroptosis-based treatment in tumors.

Regulators are accelerating new approach methodologies in cancer drug development. Their capacity to replace animal studies should depend on the context of use. Organoids, chips, and computational models can answer local, measurable questions, whereas whole-body biodistribution, immune handling, organ clearance, chronic toxicity, and therapeutic index still require integrated physiological evidence.

Cellular senescence is a stress-response program characterized by durable proliferative arrest, but senescence entry does not determine a single biological outcome. Confusion between the fate of an individual cell and the behavior of a senescent-cell population has obscured interpretation across development, ageing and disease. This Review develops a fate-resolved framework that distinguishes continued arrest, cell death, physical shedding and, under restricted conditions, sustained proliferative recovery from population-level resolution or persistence. We reserve senescence escape for sustained proliferation by the same cell or lineage after validated senescence entry; failed resolution is instead one process that can produce persistence. We examine how checkpoint integrity, chromatin organization, metabolism, secretory signaling and immune surveillance shape these outcomes in development, tissue repair, ageing-associated disorders and cancer. The strength of evidence differs sharply by context. Longitudinal cancer models provide the clearest support for strict escape, alongside a restricted developmental lineage-tracing example, whereas fibrosis, neurodegeneration and metabolic or vascular disease more often support population persistence or impaired resolution without demonstrated cell-cycle re-entry. Accordingly, static markers, single-cell and spatial profiles, and computational trajectories can identify senescence-associated states but cannot establish subsequent fate without lineage tracing, live imaging or equivalent temporal evidence. Therapeutic strategies should therefore be matched to the dominant biological problem: preserving beneficial physiological senescence, resolving or modulating harmful persistent populations, or preventing recovery of residual senescent tumour cells. Because most approaches remain preclinical or early-stage, translation will require appropriate timing, cell-type specificity and protection of beneficial senescent populations.

Gene expression profiling (GEP) provides critical insights into the cellular states, phenotypes, and biological behaviors of biological systems. However, the traditional GEP acquisition methods have significant time limitations, which directly hinder the real-time monitoring of dynamic processes, such as cell development and disease progression. In this study, we propose the biological omics sparse sensing (BoSS) framework, which effectively resolves the compatibility issue between dimensionality-reduced sampling theory and biological reaction by introducing sparse sampling strategies and noise regularization constraints. Furthermore, we have first presented rapid capture and accurate reconstruction of GEP using multiplex RT-qPCR, increasing the efficiency of transcriptome data acquisition by 60-fold. The experimental results demonstrate that when evaluating transcriptional heterogeneity in cancer tissue blocks, BoSS exhibits excellent specificity and sensitivity in clustering analysis, while fully preserving key information related to biological states, thus ensuring that the accuracy of downstream data analysis is comparable to that of ribonucleic acid (RNA)-seq. This achievement indicates that the BoSS framework is expected to play an important role in scenarios, such as intraoperative assessment of cancer progression, personalized therapy, and predictive control of biological systems.

In this issue of Cancer Cell, Kehl et al. construct a single-cell atlas of bone marrow T cells from patients with bone marrow-resident malignancies, identifying tumor-reactive populations existing in a state of latent competence. A 15-gene signature identifies this subset, which is expanded by immunotherapies and predicts clinical responses.

Severe thrombocytopenia is a known complication of menin inhibitor therapy; however, the mechanism underlying this effect is unknown. In this issue of Cancer Cell, Wen et al. demonstrate that menin is a key component of normal megakaryopoiesis and establish menin as a therapeutic vulnerability in myeloproliferative neoplasms.

In this issue of Molecular Cell, Cuneo et al.1 propose an equilibrium between two quaternary states of SPOP that can become dysregulated in cancer. SPOP oligomers form inactive double donuts or active linear filaments, as seen in gain-of-function cancer mutations.

Cellular development unfolds across both space and time, with lineage history influencing cellular identity and tissue organization. In this issue of Cell Stem Cell, Jia et al.1 combine CRISPR lineage recording with spatial transcriptomics to reconstruct the clonal relationships and spatial organization of cells during mouse development and cancer progression.

Researchers have discovered that black splotches on brown bullhead catfish in lakes in New England and Canada are likely caused by a transmissible cancer, the first one found in fish. The discovery raises questions about the cancer's origin, how it might spread, and how widespread the phenomenon might be-and could offer insights into cancer biology more broadly.